Design of Targeted Cardiovascular Molecular Imaging Probes

In vivo MRI monitoring of trafficking of dendritic cells that have taken up SPIOs in vivo after intradermal injection of labeled granulocyte–macrophage colony-stimulating (GM CSF) tumor cell vaccine into footpads of mice. For each day, magnifications of insets in A, B, C, and D are shown at right. Open arrows represent draining popliteal lymph nodes (LNs) for footpads receiving unlabeled GM CSF vaccine. Closed arrows represent draining popliteal LNs for footpads receiving SPIO-labeled GM CSF vaccine. On multigradient-echo images, SPIO-containing LNs have decreased signal intensity. (A) On day 1, popliteal LNs show no evidence of hypointensity. (B) On day 3, decreased signal intensity becomes apparent in LN corresponding to popliteal LN for SPIO-labeled vaccine. (C and D) On day 4 (C) and day 8 (D), respectively, signal decrease persists and then actually increases in popliteal LNs. Images are representative of 3 independent experiments with 5 mice each. (Reprinted with permission of (4).)

In vivo MRI of transplanted C17.2 neural stem cells, with ¹⁹F signal superimposed on ¹H MR images. (A–C) MR images at 1 h (A), 3 d (B), and 7 d (C) after injection of 4 × 10⁴ (left hemisphere, arrowhead in A) or 3 × 10⁵ (right hemisphere, arrow in A) cationic perfluoro crown ether (PFCE)–labeled cells. (E and F) Corresponding histopathology determined with phase-contrast microscopy (E) and anti–β-galactosidase immunohistochemistry (F) at day 7 shows that implanted cells remain viable and continue to produce marker enzyme. Arrow in F indicates cells migrating from injection site into brain parenchyma. (D) MR image of different animal at 14 d after injection of 4 × 10⁵ C17.2 cells into both hemispheres shows persistence of ¹⁹F signal for 2 wk. (G) Corresponding histopathology shows rhodamine fluorescence from PFCE-labeled cells colocalizing with ¹⁹F signal. Bars = 500 μm. (Reprinted with permission of (15).)

Prosthetic groups for ¹⁸F labeling of peptides and proteins. FBA = fluorobenzaldehyde; FBEM = fluorobenzamido–ethylmaleimide; FBzA = fluorobenzoic acid; FPA = fluoropropionic acid; FpyME = fluoropyridinyloxy–propylmaleimide; SFB = succinimidyl fluorobenzoate.

In vivo PET images of ¹⁸F-galacto-RGD uptake (top), ¹³N-NH3 perfusion (bottom), and their fusion (middle) in transverse views of rat heart without coronary occlusion (sham operation, left) and rat heart with 20 min of coronary occlusion 1 wk after reperfusion (right). Tracer accumulation is visible in chest wall at surgical incision area in both rats (arrowheads), but focal ¹⁸F-galacto-RGD uptake in myocardium is observed only after coronary occlusion (arrows). LCA = left anterior descending coronary artery. (Reprinted with permission of (27).)

(A–C) Typical results of hematoxylin and eosin staining of left ventricle at 24 h after ischemia (A) and detection of apoptosis in regions shown in boxes B and C (B and C). (D) Typical infarction in left ventricle at 24 h after ischemia (2,3,5-triphenyltetrazolium chloride [TTC] stain) and accumulation of ¹⁸F-annexin V. (Reprinted with permission of (28).)

Selected ¹¹C PET radiotracers for cardiac imaging.

(A) Myocardial origin of ⁶⁴Cu-DOTA-VEGF₁₂₁ PET signal after MI. (Top) Representative coregistered images from micro-CT (left), PET (right), and fused PET/CT (middle) of animal with MI. (Bottom) Representative ⁶⁴Cu-DOTA-VEGF₁₂₁ image (left), ¹⁸F-FDG image (right), and ⁶⁴Cu-DOTA-VEGF₁₂₁–¹⁸F-FDG fused image (middle). (B) Time-dependent uptake of ⁶⁴Cu-DOTA-VEGF₁₂₁. Arrowhead = area of surgical wound; red arrow = anterolateral myocardium; white arrow = intercostal muscle layer; yellow arrow = ligated coronary artery. *P < 0.05 compared with baseline. ^¶P < 0.05 compared with VEGFmutant and ⁶⁴Cu-DOTA-VEGF121. ^¥P < 0.05 compared with sham and ⁶⁴Cu-DOTA-VEGF121.

Decay-corrected whole-body coronal small-animal PET images of athymic female nude mice bearing U87MG tumors from 1-h dynamic scan and static scan at 2 h after injection of ⁶⁸Ga-NOTA-RGD1, ⁶⁸Ga-NOTA-RGD2, and ⁶⁸Ga-NOTA-RGD4 (3.7 MBq/mouse). Tumors are indicated by arrowheads.

Anteroposterior γ-image of mouse with experimental atherosclerotic lesion in left femoral artery (red arrow) and contralateral sham-treated right femoral region (yellow arrow) at 3 h after injection of ^99mTc-labeled DTPA-conjugated succinylated polylysine polymer. Injection of polymer followed pretargeting with bispecific antibody Z2D3 F(ab′)₂–anti-DTPA F(ab′)₂ (44). Lesion in left femoral artery was about 2.5 mg, as determined by immunohistochemical staining.

Schematic illustration of general core–shell morphology of multifunctional spheric nanoparticle.

Nanomaterials offering potential for high-sensitivity imaging and multimodality imaging relative to singly labeled (☆,Δ,□) targeting ligands (T).

Pegylated DOTA–shell cross-linked knedel-like nanoparticles (SCKs) originate from amphiphilic block copolymers to which are coupled desired numbers of PEG and DOTA units, so that final assembled nanoparticle has well-defined structure and quantifiable PEG and DOTA levels. Surface coverage by PEG (parameters described in table) alters biodistribution significantly. PEGylated DOTA-SCK# label under nanoparticle structure corresponds to compounds listed in table, and color code in table links nanoparticles to biodistribution bar graphs at right.

Preparation of PET nanoprobes targeted to α_vβ₃-integrin.

Cell uptake studies. (A) Percentages of total cell-associated fraction, cell-internalized fraction, and surface-bound fraction for targeted nanoprobe in α_vβ₃-integrin–positive M21 cells. (B) Percentages of cell-internalized fraction for targeted nanoprobe in absence and presence of block and nontargeted nanoprobe in α_vβ₃-integrin–positive M21 cells. All values were normalized to protein content per well. Total cell-associated fraction represents sum of cell-internalized fraction and surface-bound fraction. %ID/mg protein = percentage injected or administered dose per milligram of protein.