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WIREs Nanomed Nanobiotechnol
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Integration of gadolinium in nanostructure for contrast enhanced‐magnetic resonance imaging

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Abstract Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics, which is further enhanced with the use of contrast agents (CAs). The most commonly used CAs are gadolinium‐based contrast agents (GBCAs), in which gadolinium (Gd) is chelated with organic chelating agents (linear or cyclic). However, the use of GBCA is related to toxic side effect due to the release of free Gd3+ ions from the chelating agents. The repeated use of GBCAs has led to Gd deposition in various major organs including bone, brain, and kidneys. As a result, the use of GBCA has been linked to the development of nephrogenic systemic fibrosis (NSF). Due to the GBCA associated toxicities, some clinically approved GBCAs have been limited or revoked recently. Therefore, there is an urgent need for the development of new strategies to chelate and stabilize Gd3+ ions for contrast enhancement, safety profile, and selective imaging of a pathological site. Toward this endeavor, GBCAs have been engineered using different nanoparticulate systems to improve their stability, biocompatibility, and pharmacokinetics. Throughout this review, some of the important strategies for engineering small molecular Gd3+ chelates into a nanoconstruct is discussed. We focus on the development of GBCAs as liposomes, mesoporous silica nanoparticles (MSNs), polymeric nanocarriers, and plasmonic nanoparticles‐based design strategies to improve safety and contrast enhancement for contrast enhanced‐magnetic resonance imaging (Ce‐MRI). We also discuss the in‐vitro/in‐vivo properties of strategically designed nanoscale MRI CAs, its potentials, and limitations. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Graphical representation of the principle of MRI. (a) Longitudinal magnetization towards z‐axis, (b) transverse magnetization toward x‐axis, (c) T2‐relaxation (magnetization in the transverse direction with B0), and (d) T1‐relaxation (magnetization in the same direction with B0). Blue sphere with the arrow indicates spinning hydrogen nuclei, red and green arrows indicate the orientation of hydrogen nuclei under B0 and net magnetization, respectively
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(a) The cleavage of the PEG coating in physiological acidity triggers aggregation between Au–AZ and Au–AK via “click” cycloaddition reactions (upper panel) and due to the LPR1‐mediated, bidirectional, BBB‐traversing strategy, while the bulky AuNS aggregates are continuously trapped in tumor acidic interstitium, the intact nanoprobes in the normal brain tissue can be transported back into the bloodstream, which increases the sensitivity for the brain‐tumor margins (lower panel). (b) T1‐relaxivity of the nanoprobe mixture or Gd–DTPA as function of the incubation time at pH 5.5 (upper panel). The relaxivity was measured in a 7 T and time‐dependent Raman spectra of the mixture (0.75 × 10−9 m for each nanoprobe) measured at pH 5.5 (bottom panel). (c) Cartoons illustrating the procedure of Raman‐spectroscopy‐guided glioma resection (A) and photographs of the excised mouse brain bearing U87MG glioma xenografts and Raman spectra at the tumor site during the image‐guided tumor resection (B) surgery was conducted at 24 h PI of the Au–AZ/Au–AK mixture (1:1 M ratio, totaling 600 pmol kg−1). The intensities of the characteristic Raman twin peak were quantified in a 5 × 5 grid covering the tumor cutting bed. (Reprinted with permission from Gao et al. (). Copyright 2017 John Wiley and Sons)
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(a) Graphical representation of the NIR‐responsive gold nanorod (AuNR) surfaces that are passivated with polyethylene glycol and Gd‐DOTA‐SH forming Gd‐tethered AuNR, and (b) T1‐recovery curve of mouse melanoma (B16–F10) cell pellets treated with Gd‐AuNR (1:1 ratio) and its phantom images acquired at 14 T (insert). (Reprinted with permission from Pitchaimani et al. (). Copyright 2017 American Scientific Publishers)
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(a) Synthetic scheme of Gd‐FPNPs, (b) T1‐weighted MR images of Gd‐FPNPs with various equivalent Gd concentrations and linear correlation between longitudinal relaxivity (r1) and concentration of Gd‐FPNPs, and (c) in‐vivo T1‐weighted MR images of CT‐26 tumor‐bearing mice before and after injection of Gd‐FPNPs (0.05 mmol Gd3+ per kg) at different time points with Gadobutrol (0.05 mmol/kg) as positive control. (Reprinted with permission from Pan et al. (). Copyright 2018 American Chemical Society)
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(a) Schematic representation of the preparation of the cancer‐recognizable MRI contrast agents (CR‐CAs) as a micelles via self‐assembly of amphiphilic block copolymers (PEG‐p(l‐LA)‐DTPA‐Gd and PEG‐p(L‐His) in an aqueous solution at pH 7.4 (upper panel), and pH‐dependent structural transformation with corresponding MR signal changes via protonation of imidazole groups in PEG‐p(L‐His) at acidic pH (lower panel). (b) Schematic representation of the tumor‐accumulation behavior of (1) conventional micelle‐based CAs, (2) CR‐CAs, (c) DLS measurement of CR‐CAs colloidal dispersion at pH 7.4 and 6.5 (left) and variation of zeta‐potential measurement of CR‐CAs and insensitive‐CAs (control) as a function of pH (right), and (d) temporal color‐coded in‐vivo T1‐weighted MR images of CT26 murine tumor‐bearing Balb/c mice after the intravenous injection of CR‐CAs. (Reprinted with permission from Kyoung Sub Kim et al. (). Copyright 2014 Elsevier Ltd)
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(a) Schematic diagram for the synthetic process of MSNs‐ss‐GHA for targeting drug delivery and MR imaging. (b) and (c) are TEM images of control and targeted nanoparticles, respectively. (d) In‐vitro T1‐weighted MR images of MSN‐ss‐GHA and Gd‐DTPA at various Gd concentrations, (e–g) treatment response of different methods in 4T1tumor‐bearing mice subjected to different treatments to tumor volume, body weight change, and tumor tissue after the treatments. (Reprinted with from Chen et al. (2016). Copyright 2016 American Chemical Society)
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(a) and (b) are the schematic illustration of the synthetic strategies for the Gd3+ loaded MSNs by surface conjugation and entrapment inside core, respectively, (c) graphical representation of the synthesis of MSN–dendron–Gd (nanoprobe), (d) study of r1 obtained from the slopes of linear fits of experimental data against Gd3+ concentration used in aqueous condition where blue represents nanoprobe and back for DTPA–Gd phantom study at 0.5 T and E) in vivo T1 image of mice after injection of nanoprobe and its corresponding quantitative data. T1 image showed a brighter signal, and the analysis of its MR signal changes in the injected section when compared with PBS. (f) Showing the amount of Gd deposition in tissues after 24 hr treatment of nanoprobe and DTPA–Gd in BALB/c mice. (Reprinted with permission from Guo et al. (). Copyright 2016 The Royal Society of Chemistry)
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(a) Chemical and structural representation of conjugates used and corresponding liposomes, (b) schematic representation of the drug release and fluorescence enhancement under cellular thiols conditions, (c) in‐vivo study of signal‐to‐noise ratio (SNR) between normal and tumor area treated with different conjugates liver tissues, (d) MR images showing the livers measured at the determined times after CT26 metastatic liver tumor cells post‐inoculation where the red circles denote metastatic tumors, and (e) percentage survival rates of mice after injection showing enhanced survival with folate liposome with conjugate‐1 (FL‐1). Saline (black line), folate liposome with conjugate‐10 (FL‐10) (blue line), or FL‐1 (red line). (Reprinted with permission from Lee et al. (). Copyright 2016 American Chemical Society)
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Engineering strategies of GBCAs in nanoscale liposomal MRI CAs. (a) Post‐surface conjugation of Gd3+‐chelate with PEG similar to PEG corona formation, (b) encapsulation of Gd3+‐chelate into hydrophilic aqueous core, (c) surface conjugation of Gd3+‐chelate with lipids in lipid bilayer as a building block of liposomal system, (d) TEM image of Gd‐infused liposome with encapsulated DOX crystals, (e) hydrodynamic size demonstrating the stability of DOX containing liposomes, and (f) T1‐recovery of different Gd‐infused liposomal (Gd was infused into the lipid bilayer) formulations showing magnetic relaxivity. Inset shows the phantoms images of Gd‐containing liposomal formulations acquired at 14 T. (Reprinted with permission from Pitchaimani et al. (). Copyright 2016 The Royal Society of Chemistry)
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Timeline showing the development of GBCAs over the past 30 years. Due to Gd deposition in organs and potential toxicity, four linear GBCAs are suspended or limited for specific use in Europe.* Indicates the suspended GBCAs from the market and # indicates the limited or restricted use
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Schematics showing the different factors affecting the relaxivity of Gd3+ with the focus on water exchange mechanism. (Reprinted with permission from Debroye and Parac‐Vogt (). Copyright 2014 The Royal Society of Chemistry)
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Classification of commercially available GBCAs. The color is used to indicate the application of each class of GBCAs as discussed in the timeline
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Diagnostic Tools > Diagnostic Nanodevices
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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