Imaging Agents

Imaging cancer is crucial for guiding decisions about treatment and for monitoring the efficacy of administered therapies. The use of nanoparticles for image contrast and enhancement has enabled improvements in cancer imaging by conventional modalities, such as magnetic resonance imaging (MRI) and ultrasound, and has also established new techniques such as optical-based imaging for cancer detection.39,44,45 Targeted imaging agents that can identify specific biomarkers have the potential to improve detection, classification, and treatment of cancer with minimal invasiveness and reduced costs.

The use of nanoparticles in cancer imaging has already demonstrated clinical efficacy in detecting liver cancer and staging lymph node metastasis noninvasively.3,46 Superparamagnetic iron-oxide nanoparticles disrupt local magnetic field gradients in tissues, causing a detectable signal void in MRI. Dextran coated iron-oxide nanoparticles administered intravenously get phagocytosed by normal macrophages of the liver and lymph and the failure of these tissues to darken after iron-oxide administration identifies invading cancer cells. Directly targeting these magnetic nanoparti-cles to cancer cells has also been demonstrated. For example, herceptin mAb and folic acid on the surface of iron-oxide nanoparticles enable MRI-based molecular imaging of their respective targets

FIGURE 5.2 (See color insert following page 522.) Labeling of intracellular targets with peptide labeled quantum dots. Quantum dots (QD) modified with PEG and a nuclear localization sequence (NLS) or a mitochondrial localization sequence (MLS) were shown to target the nucleus or mitochondria of cells respectively. Seventy kilo Dalton PEG distributed in the cytoplasm contrasts nuclear localization while MitoTracker colocalizes with mitochondrial localization. (From Derfus, A. M., Chan, W. C. W., and Bhatia, S. N., Advanced Materials, 16, 961, 2004.)

FIGURE 5.2 (See color insert following page 522.) Labeling of intracellular targets with peptide labeled quantum dots. Quantum dots (QD) modified with PEG and a nuclear localization sequence (NLS) or a mitochondrial localization sequence (MLS) were shown to target the nucleus or mitochondria of cells respectively. Seventy kilo Dalton PEG distributed in the cytoplasm contrasts nuclear localization while MitoTracker colocalizes with mitochondrial localization. (From Derfus, A. M., Chan, W. C. W., and Bhatia, S. N., Advanced Materials, 16, 961, 2004.)

in tumors.47,48 Other nanoparticle cores including dendrimers, micelles, and liposomes modified with paramagnetic gadolinium have also been used for tumor targeted MRI contrast.48-50

Gold nanoshells offer a promising alternative to MRI probes by providing contrast for optical imaging.45 These nanoparticles are constructed from a dielectric core (silicon) and a metallic conducting shell (gold). By varying the dimension of the core and shell, the plasmon resonance of these particles can be engineered to either absorb or scatter wavelengths of light, from UV to infrared. Particles that are tailored to scatter light in the near-infrared, where tissues have minimal absorbance, have been used to enhance imaging modalities such as reflectance confocal microscopy and optical coherence tomography (OCT).51 Although the penetration of optical techniques does not approach that of CT or MRI, imaging features is possible at depths of a few centimeters. Gold colloids have also been used for optical contrast, but these lack the inherent tunability of nanoshells. The conjugation of optical contrast agents to antibodies has been used for the molecular imaging of the EGFR receptor on early cervical precancers and for Her2 + breast carcinoma cells in mice.52,53

Fluorescent nanoparticles offer another useful tool to enhance optical detection. These probes are identified easily in microscopy and are useful for tracking the biodistribution of nanoparticles in experimental models. Fluorescent semiconductor nanocrystals, quantum dots, have been used to show ligand-mediated nanoparticle targeting to distinct features in the tumor.6 Three different phage display-derived peptides were used to specifically target these nanocrystals to tumor blood vessels, tumor lymphatics, or lung endothelium (Figure 5.3). Functionalization of these nanopar-ticles with PEG eliminated detectable accumulation in RES organs, including the liver (Figure 5.4). Quantum dots have a distinct advantage over conventional fluorophores because

FIGURE 5.3 (See color insert following page 522.) Noninvasive detection of lymph node metastasis with iron-oxide nanoparticles and MRI. (a) A three-dimensional reconstruction using nanoparticle-enhanced MRI of the prostate. Metastatic lymph nodes are in red and normal nodes are in green. (b) Conventional MRI image shows similar signal intensity from two adjacent nodes. (c) Nanoparticle-enhanced MRI shows a decreased signal in the normal node from macrophage uptake (thick arrow), but not in the metastatic node (thin arrow). (From Harisinghani, M. G. and Weissleder, R., Plos Medicine, 1, 202-209, 2004.)

FIGURE 5.3 (See color insert following page 522.) Noninvasive detection of lymph node metastasis with iron-oxide nanoparticles and MRI. (a) A three-dimensional reconstruction using nanoparticle-enhanced MRI of the prostate. Metastatic lymph nodes are in red and normal nodes are in green. (b) Conventional MRI image shows similar signal intensity from two adjacent nodes. (c) Nanoparticle-enhanced MRI shows a decreased signal in the normal node from macrophage uptake (thick arrow), but not in the metastatic node (thin arrow). (From Harisinghani, M. G. and Weissleder, R., Plos Medicine, 1, 202-209, 2004.)

of their size-tunable excitation and emission profiles, narrow bandwidths, and high photo-stability. , Using nanocrystals that fluoresce in the near-infrared could extend their utility to clinical settings,56 though a key limitation has been their potential toxicity because they are formulated from heavy metals.57 Efforts to make these of nontoxic materials are ongoing (Figure 5.4). Alternative fluorescent nanoparticle probes have been developed including fluorescently tagged dendrimers and fluorophore-embedded silica nanoparticles. -

Nanoparticle formulations that provide contrast for other imaging modalities including ultrasound and CT have been described. Perfluorocarbon emulsion nanoparticles composed of lipid-encapsulated perfluorocarbon liquid, about 250 nm diameter, are effective in giving echo contrast.61 Air-entrapping liposomes formulated from freeze-drying techniques have also been developed to give ultrasound contrast.62,63 These agents passively distribute in RES organs and areas of angio-genenis enabling enhanced imaging of these features. Bismuth sulfide nanoparticles can be used as contrast agents for CT imaging, giving blood pool contrast similar to that of iodine but at lower concentrations. These can also be used to image lymph nodes after phagocytic uptake.64 As with other imaging modalities, the attachment of appropriate ligands to nanoparticle-based CT and ultrasound contrast agents could be used for molecular imaging.

An interesting extension of the imaging agents described above is their combination into multimodal imaging nanoparticles. The combination of fluorescence and magnetic properties within a single particle has been used for dual optical and MRI imaging. Fluorescence is used to determine the localization of targeted imaging agents down to specific micro-structures inside and outside cells and magnetic domains provide three-dimensional whole-body imaging capabilities with MRI.59,65 These magneto-fluorescent nanoparticles could be effective for image guided surgeries where MRI is used to locate cancer in the body and fluorescence is used to more precisely

FIGURE 5.4 (See color insert following page 522.) Targeting quantum dots (QDs) to site-specific endothelium with phage display-derived peptides. (a) Schematic representation of co-injected red and green quantum dots that home to tumor and lung vasculature respectively after intravenous injection. (b) Schematic representation of peptide-coated QDs and peptide-coated PEG-QDs. (c) QDs labeled with the tumor endothelium homing peptide F3 co-localize with a blood vessel marker. (d) QDs labeled with the tumor lymphatic homing peptide Lyp-1 highlight the endothelium but do not colocalize with a blood vessel marker. (From Akerman, M. E., Chan, W. C. W., Laakkonen, P., Bhatia, S. N., and Ruoslahti, E., Proceedings of the National Academy of Sciences of the United States of America, 99, 12617-12621, 2002.)

FIGURE 5.4 (See color insert following page 522.) Targeting quantum dots (QDs) to site-specific endothelium with phage display-derived peptides. (a) Schematic representation of co-injected red and green quantum dots that home to tumor and lung vasculature respectively after intravenous injection. (b) Schematic representation of peptide-coated QDs and peptide-coated PEG-QDs. (c) QDs labeled with the tumor endothelium homing peptide F3 co-localize with a blood vessel marker. (d) QDs labeled with the tumor lymphatic homing peptide Lyp-1 highlight the endothelium but do not colocalize with a blood vessel marker. (From Akerman, M. E., Chan, W. C. W., Laakkonen, P., Bhatia, S. N., and Ruoslahti, E., Proceedings of the National Academy of Sciences of the United States of America, 99, 12617-12621, 2002.)

delineate tumor borders during resection. Other dual-imaging probes have been described including: perfluorocarbon emulsions tagged with gadolinium for combined ultrasound and MRI.66

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