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Manganese-containing Prussian blue nanoparticles for imaging of pediatric brain tumors.

Dumont MF, Yadavilli S, Sze RW, Nazarian J, Fernandes R - Int J Nanomedicine (2014)

Bottom Line: Both neuron-glial antigen 2 and the transferrin receptor are protein markers overexpressed in PBTs.We describe the synthesis, biofunctionalization, and characterization of these multimodal nanoparticles.Further, we demonstrate the MRI and fluorescence imaging capabilities of manganese-containing Prussian blue nanoparticles in vitro.

View Article: PubMed Central - PubMed

Affiliation: Sheikh Zayed Institute for Pediatric Surgical Innovation, Washington, DC, USA.

ABSTRACT
Pediatric brain tumors (PBTs) are a leading cause of death in children. For an improved prognosis in patients with PBTs, there is a critical need to develop molecularly-specific imaging agents to monitor disease progression and response to treatment. In this paper, we describe manganese-containing Prussian blue nanoparticles as agents for molecular magnetic resonance imaging (MRI) and fluorescence-based imaging of PBTs. Our core-shell nanoparticles consist of a core lattice structure that incorporates and retains paramagnetic Mn(2+) ions, and generates MRI contrast (both negative and positive). The biofunctionalized shell is comprised of fluorescent avidin, which serves the dual purpose of enabling fluorescence imaging and functioning as a platform for the attachment of biotinylated ligands that target PBTs. The surfaces of our nanoparticles are modified with biotinylated antibodies targeting neuron-glial antigen 2 or biotinylated transferrin. Both neuron-glial antigen 2 and the transferrin receptor are protein markers overexpressed in PBTs. We describe the synthesis, biofunctionalization, and characterization of these multimodal nanoparticles. Further, we demonstrate the MRI and fluorescence imaging capabilities of manganese-containing Prussian blue nanoparticles in vitro. Finally, we demonstrate the potential of these nanoparticles as PBT imaging agents by measuring their organ and brain biodistribution in an orthotopic mouse model of PBTs using ex vivo fluorescence imaging.

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Molecular MRI-based detection of PBT cells using biofunctionalized Prussian blue nanoparticles. (A) T1-weighted and T2-weighted contrast enhancement in phantoms comprised of a fixed number of BSG D10 treated with MnPB-A488-ANG2 (n=6), MnPB-A488-AbC (n=3), or MnPB-A488 (no antibody, triplicate). (B) Normalized fluorescence signal intensity (au) for BSG D10 treated with ANG2, AbC, and no antibody-modified MnPB-A488. **P<0.05.Abbreviations: MnPB, manganese-containing Prussian blue; A488, avidin-Alexa Fluor 488; ANG2, anti-neuron-glial antigen 2; AbC, eotaxin antibody; BSG, brainstem glioma; T1W, T1-weighted; T2W, T2-weighted; PBT, pediatric brain tumor; au, arbitrary units; Ab, antibody; MRI, magnetic resonance imaging.
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f5-ijn-9-2581: Molecular MRI-based detection of PBT cells using biofunctionalized Prussian blue nanoparticles. (A) T1-weighted and T2-weighted contrast enhancement in phantoms comprised of a fixed number of BSG D10 treated with MnPB-A488-ANG2 (n=6), MnPB-A488-AbC (n=3), or MnPB-A488 (no antibody, triplicate). (B) Normalized fluorescence signal intensity (au) for BSG D10 treated with ANG2, AbC, and no antibody-modified MnPB-A488. **P<0.05.Abbreviations: MnPB, manganese-containing Prussian blue; A488, avidin-Alexa Fluor 488; ANG2, anti-neuron-glial antigen 2; AbC, eotaxin antibody; BSG, brainstem glioma; T1W, T1-weighted; T2W, T2-weighted; PBT, pediatric brain tumor; au, arbitrary units; Ab, antibody; MRI, magnetic resonance imaging.

Mentions: To evaluate MnPB-A488-ANG2 nanoparticles as molecularly-targeted MRI agents for detecting PBT cells, we contacted BSG D10 cells with MnPB-A488-ANG2 (n=6), with MnPB-A488-AbC (n=3), and with MnPB-A488 (n=3); we then scanned the sample-containing phantoms, and obtained T1-weighted and T2-weighted images (Figure 5). The MnPB-A488-ANG2 nanoparticles bound to the BSG D10 cells and generated hyperintensity (augmentation of the signal) in the T1-weighted images and hypointensity (attenuation of the signal) in the T2-weighted images (Figure 5A). Control (MnPB-A488-AbC [control antibody] and MnPB-A488 [no antibody]) nanoparticles exhibited negligible binding to BSG D10 and the observed changes in magnetic resonance signal intensity were modest (Figure 5A). Quantitative analysis of the T1-weighted images showed that the MnPB-A488-ANG2 nanoparticles bound to BSG D10 and were distinctly detected (signal intensity of 94 au). The controls (MnPB-A488-AbC and MnPB-A488) showed background contrast levels, ie, a signal intensity of ~10 au (Figure 5B). Signal intensity quantification of the T2-weighted images confirmed that MnPB-A488-ANG2 nanoparticles specifically bound to BSG D10 as it generated hypointensity (signal intensity of 41 au). The controls (MnPB-A488-AbC and MnPB-A488) did not display significant attenuation of the signal (107 and 75, respectively; Figure 5B). These results demonstrated the feasibility of detecting PBT cells using our biofunctionalized MnPB nanoparticles in both T1-weighted and T2-weighted images.


Manganese-containing Prussian blue nanoparticles for imaging of pediatric brain tumors.

Dumont MF, Yadavilli S, Sze RW, Nazarian J, Fernandes R - Int J Nanomedicine (2014)

Molecular MRI-based detection of PBT cells using biofunctionalized Prussian blue nanoparticles. (A) T1-weighted and T2-weighted contrast enhancement in phantoms comprised of a fixed number of BSG D10 treated with MnPB-A488-ANG2 (n=6), MnPB-A488-AbC (n=3), or MnPB-A488 (no antibody, triplicate). (B) Normalized fluorescence signal intensity (au) for BSG D10 treated with ANG2, AbC, and no antibody-modified MnPB-A488. **P<0.05.Abbreviations: MnPB, manganese-containing Prussian blue; A488, avidin-Alexa Fluor 488; ANG2, anti-neuron-glial antigen 2; AbC, eotaxin antibody; BSG, brainstem glioma; T1W, T1-weighted; T2W, T2-weighted; PBT, pediatric brain tumor; au, arbitrary units; Ab, antibody; MRI, magnetic resonance imaging.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043710&req=5

f5-ijn-9-2581: Molecular MRI-based detection of PBT cells using biofunctionalized Prussian blue nanoparticles. (A) T1-weighted and T2-weighted contrast enhancement in phantoms comprised of a fixed number of BSG D10 treated with MnPB-A488-ANG2 (n=6), MnPB-A488-AbC (n=3), or MnPB-A488 (no antibody, triplicate). (B) Normalized fluorescence signal intensity (au) for BSG D10 treated with ANG2, AbC, and no antibody-modified MnPB-A488. **P<0.05.Abbreviations: MnPB, manganese-containing Prussian blue; A488, avidin-Alexa Fluor 488; ANG2, anti-neuron-glial antigen 2; AbC, eotaxin antibody; BSG, brainstem glioma; T1W, T1-weighted; T2W, T2-weighted; PBT, pediatric brain tumor; au, arbitrary units; Ab, antibody; MRI, magnetic resonance imaging.
Mentions: To evaluate MnPB-A488-ANG2 nanoparticles as molecularly-targeted MRI agents for detecting PBT cells, we contacted BSG D10 cells with MnPB-A488-ANG2 (n=6), with MnPB-A488-AbC (n=3), and with MnPB-A488 (n=3); we then scanned the sample-containing phantoms, and obtained T1-weighted and T2-weighted images (Figure 5). The MnPB-A488-ANG2 nanoparticles bound to the BSG D10 cells and generated hyperintensity (augmentation of the signal) in the T1-weighted images and hypointensity (attenuation of the signal) in the T2-weighted images (Figure 5A). Control (MnPB-A488-AbC [control antibody] and MnPB-A488 [no antibody]) nanoparticles exhibited negligible binding to BSG D10 and the observed changes in magnetic resonance signal intensity were modest (Figure 5A). Quantitative analysis of the T1-weighted images showed that the MnPB-A488-ANG2 nanoparticles bound to BSG D10 and were distinctly detected (signal intensity of 94 au). The controls (MnPB-A488-AbC and MnPB-A488) showed background contrast levels, ie, a signal intensity of ~10 au (Figure 5B). Signal intensity quantification of the T2-weighted images confirmed that MnPB-A488-ANG2 nanoparticles specifically bound to BSG D10 as it generated hypointensity (signal intensity of 41 au). The controls (MnPB-A488-AbC and MnPB-A488) did not display significant attenuation of the signal (107 and 75, respectively; Figure 5B). These results demonstrated the feasibility of detecting PBT cells using our biofunctionalized MnPB nanoparticles in both T1-weighted and T2-weighted images.

Bottom Line: Both neuron-glial antigen 2 and the transferrin receptor are protein markers overexpressed in PBTs.We describe the synthesis, biofunctionalization, and characterization of these multimodal nanoparticles.Further, we demonstrate the MRI and fluorescence imaging capabilities of manganese-containing Prussian blue nanoparticles in vitro.

View Article: PubMed Central - PubMed

Affiliation: Sheikh Zayed Institute for Pediatric Surgical Innovation, Washington, DC, USA.

ABSTRACT
Pediatric brain tumors (PBTs) are a leading cause of death in children. For an improved prognosis in patients with PBTs, there is a critical need to develop molecularly-specific imaging agents to monitor disease progression and response to treatment. In this paper, we describe manganese-containing Prussian blue nanoparticles as agents for molecular magnetic resonance imaging (MRI) and fluorescence-based imaging of PBTs. Our core-shell nanoparticles consist of a core lattice structure that incorporates and retains paramagnetic Mn(2+) ions, and generates MRI contrast (both negative and positive). The biofunctionalized shell is comprised of fluorescent avidin, which serves the dual purpose of enabling fluorescence imaging and functioning as a platform for the attachment of biotinylated ligands that target PBTs. The surfaces of our nanoparticles are modified with biotinylated antibodies targeting neuron-glial antigen 2 or biotinylated transferrin. Both neuron-glial antigen 2 and the transferrin receptor are protein markers overexpressed in PBTs. We describe the synthesis, biofunctionalization, and characterization of these multimodal nanoparticles. Further, we demonstrate the MRI and fluorescence imaging capabilities of manganese-containing Prussian blue nanoparticles in vitro. Finally, we demonstrate the potential of these nanoparticles as PBT imaging agents by measuring their organ and brain biodistribution in an orthotopic mouse model of PBTs using ex vivo fluorescence imaging.

Show MeSH
Related in: MedlinePlus