We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.

The new compound is potentially useful for the diagnosis of vulnerable atherosclerotic plaques and of other pathologies characterized by alpha v beta3 integrin expression, such as cancer and inflammation. The delayed blood clearance, the significant enhancement of the signal-to-noise ratio, and the low immunogenicity of the mimetic molecule highlight its potential for an industrial and clinical implementation.

In this study 'second generation' AnxV was specifically labeled with (99m)Tc in three different ways outside the binding region of the protein to obtain an improved target-to-background activity ratio. The compounds were tested in vitro and in vivo in normal mice and in a model of hepatic apoptosis (anti-Fas mAb). The apoptosis binding was most prominent for the HIS-tagged 'second generation' AnxV labeled with (99m)Tc(CO)(3) in comparison to (99m)Tc-HYNIC-cys-AnxV and (99m)Tc(CO)(3)-DTPA-cys-AnxV.

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Re- and Tc-complexes of the oxidation state (+I) offer a useful synthetic pool for the labeling of biomolecules due to their co-ordination properties and stability, which are superior to compounds of the oxidation state (+V). Based on the results for Tc-tricarbonyl complexes it was the topic of this work to develop an access to similar but higher charged compounds, which could be performed by replacing a neutral [CO]-group by a [NO](+)-group. The resulting Re(I)- and Tc(I)-dicarbonyl-nitrosyl complexes, such as [N(CH2CH3)4][ReX3(CO)2(NO)], show a tendency for co-ordination at carboxylic and amine groups of biomolecules (X = Br, Cl). This was shown with picolinic acid (H-pic), a suitable model for amino acids, forming the neutral complex [ReX(pic)(CO)2(NO)]. In a similar fashion conjugation of [188Re(CO)2(NO)](2+)- or [99mTc(CO)2(NO)](2+)-compounds to proteins or antibodies is feasible. This approach opens a way to a potentially new class of radiopharmaceuticals.

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Due to its biodistribution, radiation absorbed organ doses, low toxicity and clinical data, myeloablative radioimmunotherapy with 188Re-labeled anti-CD66 mAb seems to be a promising method for improving standard conditioning of high-risk leukemia patients prior to SCT.