Growth factor/peptide receptor imaging for the development of targeted therapy in oncology.

Receptor imaging by means of positron emission tomography (PET) and single photon emission computerized tomography (SPECT) may non-invasively address questions that are essential to the development and the clinical application of drugs targeting receptors expressed on human malignancies : is the receptor targeting drug getting to the tumor in the required concentration, is there a heterogeneity in tumor uptake, how fast is the drug cleared from the tumor and how is the receptor targeting drug metabolized. Such information may be used to assess the efficacy of strategies that aim to improve drug penetration through tumor tissue or to select compounds based on their ability to penetrate tumor tissue, thereby increasing the therapeutic index. In addition, imaging by means of PET and SPECT with receptor targeting radiopharmaceuticals may allow for the selection of patients that may benefit from receptor targeting therapies either ab initio, in the situation where the levels of receptor expression are proportional to the level of signaling via the receptor, or through sequential imaging in the situation where the level of receptor expression is not proportional to the level of signaling via the receptor and proof of down-regulation of the number of receptors is required.

Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy.

OBJECTIVES: This study sought to evaluate the feasibility of noninvasive detection of matrix metalloproteinase (MMP) activity in experimental atherosclerosis using technetium-99m-labeled broad matrix metalloproteinase inhibitor (MPI) and to determine the effect of dietary modification and statin treatment on MMP activity. BACKGROUND: The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture. METHODS: Atherosclerosis was produced in 34 New Zealand White rabbits by balloon de-endotheliazation of the abdominal aorta and a high-cholesterol diet. In addition, 12 unmanipulated rabbits were used as controls and 3 for blood clearance characteristics. In vivo micro-single-photon emission computed tomography (SPECT) imaging was performed after radiolabeled MPI administration. Subsequently, aortas were explanted to quantitatively measure percent injected dose per gram (%ID/g) MPI uptake. Histological and immunohistochemical characterization was performed and the extent of MMP activity was determined by gel zymography or enzyme-linked immunosorbent assays. RESULTS: The MPI uptake in atherosclerotic lesions (n = 18) was clearly visualized by micro-SPECT imaging; MPI uptake was markedly reduced by administration of unlabeled MPI before the radiotracer (n = 4). The MPI uptake was also significantly reduced after diet withdrawal (n = 6) and fluvastatin treatment (n = 6); no uptake was observed in normal control rabbits (n = 12). The %ID/g MPI uptake (0.10 +/- 0.03%) in the atherosclerotic lesions was significantly higher than the uptake in control aorta (0.016 +/- 0.004%, p < 0.0001). Uptake in fluvastatin (0.056 +/- 0.011%, p < 0.0005) and diet withdrawal groups (0.043 +/- 0.011%, p < 0.0001) was lower than the untreated group. The MPI uptake correlated with immunohistochemically verified macrophage infiltration (r = 0.643, p < 0.0001), and MMP-2 (r = 0.542, p < 0.0001) or MMP-9 (r = 0.578, p < 0.0001) expression in plaques. CONCLUSIONS: The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.