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Peripheral benzodiazepine receptors (PBRs, also named TSPO) are overexpressed in many tumor types, with the grade of TSPO overexpression correlating with the malignancy of the tumor. For this reason, TSPO-binding ligands have been widely explored as carriers for receptor-mediated drug delivery. In this paper we have selected a ligand with nanomolar affinity for TSPO, [2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-n-propylacetamide (3), for preparing platinum adducts that are structural analogues to picoplatin, cis-[PtCl(2)(NH(3))(2-picoline)] (AMD0473, 6), a platinum analogue currently in advanced clinical investigation. In vitro studies assessing receptor binding and cytotoxicity against human and rat glioma cells have shown that the new compounds cis-[PtX(2)(NH(3)){[2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-n-propylacetamide}] (X = I, 4; X = Cl, 5) keep high affinity and selectivity for TSPO (nanomolar concentration) and are as cytotoxic as cisplatin. Moreover, they appear to be equally active against sensitive and cisplatin-resistant A2780 cells. Similar to cisplatin, these compounds induce apoptosis but show a favorable 10- to 100-fold enhanced accumulation in the glioma cells.

A peripheral benzodiazepine receptor (PBR) ligand (TZ6, 5) has been selected as receptor-mediated carrier for antitumor cisplatin-like compounds. Compound 5, containing a thiazole ring in position 2 of the imidazopyridine nucleus, is able to act as a dinitrogen chelate toward platinum. The resulting complex, cis-[PtCl2(5)], that is, compound 8, has been fully characterized by NMR techniques and has been shown to possess affinity and selectivity for the PBR comparable to those of 5 (IC50 of 4.6 and 2.81 nM for 8 and 5, respectively; selectivity indexes for PBR greater than 10,000 for both compounds). Hence, a platinum moiety cross-linking the imidazopyridine and the thiazole aromatic rings does not alter the affinity for PBR. The same cross-linking could be responsible for the tendency of 8 to associate in dimers. The equilibrium between monomer and dimer has been investigated by NMR spectroscopy and the corresponding constant determined.

Bisphosphonates (BPs), the synthetic analogues of pyrophosphate, are widely used in the treatment of metabolic bone diseases. BPs exhibit a preferential accumulation in malignant pleural mesothelioma (MPM) and, furthermore, nitrogen-containing BPs (n-BPs) show significant inhibition of MPM cell proliferation. We synthesised dinuclear platinum(II) complexes containing a n-BP moiety as bridging ligand and am(m)ines as terminal ligands (Pt–n-BP)s, with the aim of obtaining bifunctional mesothelioma-targeted drugs. We compared the antiproliferative effect of the single drugs (i.e. Pt-model and n-BPs) with that of the preformed Pt–n-BP complexes by means of the combination index (CI) in order to assess the synergistic/additive/antagonistic effect of the two constituents in the resulting conjugates. The combination of the two individual drugs was almost additive, while the preformed Pt–n-BP produced an antagonistic effect. Furthermore, (Pt–n-BP)s neither inhibited the mevalonate pathway (as n-BPs normally do) nor increased the Pt uptake. The minimal biological results of these conjugates could be traced back to a slow and inappropriate hydrolysis, that does not split the adduct into active components.

For over 30 years cisplatin has been one of the most active antitumour agents in clinical use, nevertheless research for overcoming cisplatin toxicity and resistance or for improving its efficacy has never ceased. In this context we have recently proposed dinuclear Pt complexes with bridging geminal bisphosphonates as novel Pt-prodrugs with potential activity at the bone surface after embedment in inorganic matrices and implantation at the tumour site. In the present paper we report the synthesis and full characterization of four new platinum complexes having a dinuclear structure with a bisphosphonate (2-ammonium-1-hydroxyethane-1,1-diyl-bisphosphonate or 3-ammonium-1-hydroxypropane-1,1-diyl-bisphosphonate, AHBP-H and PAM-H, respectively) acting as a bridging ligand between two platinum moieties (cis-[Pt(NH(3))(2)](2+), directly related to cisplatin, and [Pt(cis-1,4-DACH)](2+), known to be able to overcome the cisplatin resistance). Moreover, as a preliminary investigation, the in vitro cytotoxicity of the new complexes has been evaluated on a panel of 13 human tumour cell lines including cisplatin- and multidrug-resistant sublines.

This study widens the role of biomimetic hydroxyapatite (HA) nanocrystals as bone substitutes and describes how they can be used as bone-specific drug delivery devices for in situ treatment of bone tumors upon local implantation. The adsorption and release kinetics of bis-{ethylenediamineplatinum(II)}-2-amino-1-hydroxyethane-1,1-diyl-bisphosphonate and bis-{ethylenediamineplatinum(II)}medronate on two kinds of HA nanocrystals having different morphologies, crystallinity degrees and surface areas have been investigated. The different chemical structures of the two Pt complexes appreciably affect not only the affinity towards the two kinds of HA, but also their release. The Pt complex loading is slightly greater for the HA characterized by lower crystallinity and higher surface area, with respect to the more crystalline one. The cytotoxicity of Pt complexes released from the HA were tested against human cervix carcinoma cells and, interestingly, were found to be more cytotoxic than the unmodified complexes. The released Pt species are therefore the active dichloridoethylenediamineplatinum(II) or related solvato species formed by Pt-bisphosphonate bond breaking.

Although mammary pain is the most common reason prompting women to seek breast examination, it is considered to unimportant to be fully investigated and often treatment is extremely superficial. A projected investigation of the natural history of mammary pain through examination of the symptomatology of the commonest forms is considered to be necessary for accurate diagnosis, itself indispensable for effective treatment.