Uses of Nanoparticles for Central Nervous System Imaging and Therapy

Nanoparticles containing therapeutic drugs against a tumor may reach their target by using either passive targeting or active targeting (ie, by using ligands that are tumor-specific). A, Passive tumor deposition by nontargeted nanoparticles (ie, nanoparticles that are not coated with antibody against tumor cells) is accomplished by extravasation from leaky vessels adjacent to the tumor and retention of nanoparticles at the tumor site due to slow clearance. Note that, in this diagram, nanoparticles have accumulated in the extracellular environment, rather than within tumor cells. B, Active targeting by the same quantum dots as in A but to which an antibody targeted against tumor cells has been added to the surface of the nanoparticle. Note that, in this example, nanoparticles again extravasate through leaky peritumoral vessels, but due to active targeting, they accumulate on tumor cell membranes and are incorporated within tumor cells. QD indicates quantum dots. Reprinted with permission from Macmillan Publishers Ltd; Nature Biotechnology 2004;22:969-76, copyright 2004.

Use of dual-purpose nanoparticles to image neuroblastoma cells by both fluorescence imaging and MR imaging. The nanoparticles are coated with an antibody that binds to polysialic acids on neuroblastoma cell surfaces. A, Diagram showing components of nanoparticle, with water soluble iron oxide particles conjugated to the surface of a rhodamine dye-doped silica core by using cross-linkers (shown in pink). B, Transmission electron microscopy image of nanoparticles shows that the constellation of iron oxide particles (black) bound to the surface dye-doped silica core (gray) measures approximately 30 nm in diameter (inset). C, Fluorescence imaging of dual-purpose nanoparticles bound to neuroblastoma cells that overexpress polysialic acids shows the nanoparticle-bound cells in red. D, T2*-weighted MR image shows the same cells as shown in A as dark regions due to susceptibility effect of Fe₃O₄ molecules on nanoparticle surface. Reprinted with permission from Lee JH, Jun YW, Yeon SI, et al. Dual-mode nanoparticle probes for high-performance magnetic resonance and fluorescence imaging of neuroblastoma. Angew Chem Int Ed Engl 2006;45:8160–62. Copyright Wiley-VCH, Verlag GmbH & Co. KGaA.

Use of nanoparticles to image astrocytes. Staining of cortical astrocytes by antibody-conjugated nanoparticles that cross-react with glial fibrillary acidic protein is depicted. Reprinted with permission from J Neurosci 2006;26:1893–95.

Use of quantum dots to track the lateral mobility of neurotransmitter receptors over the surface of a neurite, which is important for understanding development and plasticity of synapses. Images are derived from a series of 850 images obtained during 60 seconds. Quantum dots coated with antibody to glycine receptor are shown in green, and synaptic boutons marked by FM4–64 dye are depicted in red. A, Early in the sequence, a glycine receptor (arrow) is seen adjacent to a synaptic bouton (b1). Two other synaptic boutons are labeled b2 and b3. Another glycine receptor (arrowhead) is seen adjacent to synaptic bouton b3. B, Approximately 8 seconds later, the glycine receptor previously located at synaptic bouton b1 has migrated to a position in the center of the field. The glycine receptor at synaptic bouton b3 has remained stationary. C, At the end of 1 minute, the glycine receptor originally located at synaptic bouton b1 in A has migrated to synaptic bouton b2. From Dahan M, Levi S, Luccardini C, et al. Diffusion dynamics of glycine receptors revealed by single-quantum dot tracking. Science 2003; 302:442–45. Reprinted with permission from AAAS.

Comparison of tumor-targeted (chlorotoxin-conjugated) and nontargeted superparamagnetic nanoparticles for detection of a 9L glioma xenograft grown in the flank of a mouse. A, Transmission electron microscope image of a 9L tumor cell incubated with superparamagnetic nanoparticles that are not targeted specifically against tumor cells shows relatively few nanoparticles (black dots) within the cell. B, Transmission electron microscope image of a 9L tumor cell incubated with tumor-targeted superparamagnetic nanoparticles shows prominent intracellular uptake of nanoparticles (black dots). C, Axial MR image of a mouse shows relatively sparse uptake of nontargeted nanoparticles (colored regions) within the tumor. Relatively low uptake is depicted in blue and slightly higher uptake, in yellow. D, Axial MR image of a different tumor-bearing mouse than that depicted in C shows marked uptake of tumor-targeted nanoparticles (colored regions) within the tumor. Note the relatively large percentage of red and orange pixels indicating high uptake (see color scale). Reprinted with permission from Sun C, Veiseh O, Gunn J, et al. In vivo MRI detection of gliomas by chlorotoxin-conjugated superparamagnetic nanoprobes. Small 2008; 4:372-79. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.