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We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν)β(3) . Because α(ν)β(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68)Ga complexation for the promising (68)Ga-PET technique; the AAZTA complex 15((68)Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity.

As compared to similar imaging approaches using the (18)F-galacto-derivative, we documented for the first time with microPET/CT imaging the (68)Ga-NOTA-RGD derivative that appears eligible for PET imaging in animal models of vascular remodelling during evolving MI. The simple chemistry employed to synthesize the (68)Ga-based radiotracer may greatly facilitate its translation to a clinical setting.

In recent years progress has been speeding in studies of cell-cell interaction governed by adhesion molecules, and in particular by integrins and their ligands in cells and in the extracellular matrix. Integrins are distributed in a variety of tissues and blood cells. An increased expression of integrins and of their adhesion counterparts is often observed in sites relevant to disease states. Important roles are played by integrin α(v)β(3) in cancer angiogenesis and metastatic diffusion, in angiogenesis in ischemic tissues, in atherosclerotic damage and restenosis, and in osteoporosis; by integrin α(5)β(1) in angiogenesis processes; by integrin α(II)bβ(3), mediating adhesion of platelets to fibrinogen, in thrombotic conditions; by integrins α(4)β(1) and α(L)β(2) in inflammatory conditions, particularly autoimmune diseases and asthma. Therefore, medicinal chemists became attracted and engaged in research on integrins as therapeutic and diagnostic targets. Many efforts have been directed towards the development of molecular constructs including integrin ligands that can provide advanced tools for drug delivery, for imaging, or for their combination (theranostics), particularly by exploiting the new possibilities offered by nanoparticles. Here we will review the current status and the future perspective of integrin targeting of several kind of nanoparticles, going from most studied micelles, liposomes, polymeric nanoparticles to finish with inorganic nanoparticles of more recent employment. Perfluoroalkane filled microbubbles, although over the nanometric size (1-10 μm) will be shortly considered.

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