The direct mapping of the uptake of platinum anticancer agents in individual human ovarian adenocarcinoma cells using a hard X-ray microprobe.

Uptake of platinum-based anticancer compounds into individual human ovarian andenocarcinoma cells was measured using an X-ray microprobe. The uptake of cisplatin, a platinum-based compound, in drug-resistant cells is decreased by approximately 50% after 24 h, compared with the uptake of the drug in nonresistant cells over the same time period. The Pt103 derivative of the drug, in contrast, showed an increased uptake by an order of magnitude in resistant cells over the same time period. Increased uptake appears to allow Pt103 to overcome the resistance mechanism developed by the cell. This work additionally shows that the X-ray microprobe is able to directly quantify Pt drug uptake on a subcellular level and can measure the mass of Pt down to a detectable limit of 20 attograms of Pt (2 x 10(-17) grams or 6 x 10(4) Pt atoms) in 1 s. Such exquisite elemental sensitivity combined with high spatial resolution paves the way for quantitative submicron three-dimensional mapping of elemental distributions within individual cells.

Systematic differences in electrochemical reduction of the structurally characterized anti-cancer platinum(IV) complexes [Pt{((p-HC6F4)NCH2)2}-(pyridine)2Cl2], [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)2], and [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)Cl].

The putative platinum(IV) anticancer drugs, [Pt{((R)NCH(2))(2)}(py)(2)XY] (X,Y=Cl, R=p-HC(6)F(4) (1a), C(6)F(5) (1b); X,Y=OH, R=p-HC(6)F(4) (2); X=Cl, Y=OH, R=p-HC(6)F(4) (3), py = pyridine) have been prepared by oxidation of the Pt(II) anticancer drugs [Pt{((R)NCH(2))(2)}(py)(2)] (R=p-HC(6)F(4) (4a) or C(6)F(5) (4b)) with PhICl(2) (1a,b), H(2)O(2) (2) and PhICl(2)/Bu(4)NOH (3). NMR spectroscopy and the X-ray crystal structures of 1b, 2 and 3 show that they have octahedral stereochemistry with the X,Y ligands in the trans-position. The net two electron electrochemical reduction of 1a, 2 and 3 has been studied by voltammetric, spectroelectrochemical and bulk electrolysis techniques in acetonitrile. NMR and other data reveal that reduction of 1a gives pure 4a via the elimination of both axial chloride ligands. In the case of 2, one end of the diamide ligand is protonated and the resulting -NH(p-HC(6)F(4)) group dissociated giving a [Pt{N(p-HC(6)F(4))CH(2)CH(2)NH(p-HC(6)F(4))}] arrangement, one pyridine ligand is lost and a hydroxide ion retained in the coordination sphere. Intriguingly, in the case of reduction of 3, a 50% mixture of the reduction products of pure 1a and 2 is formed. The relative ease of reduction is 1>3>2. Testing of 1a, 2 and 3 against L1210 and L1210(DDP) (DDP = cis-diamine-dichloroplatinum(II)) mouse leukaemia cells shows all to be cytotoxic with IC(50) values of 1.0-3.5 µM. 2 and 3 are active in vivo against AHDJ/PC6 tumor line when delivered in peanut oil despite being hard to reduce electrochemically, and notably are more active than 4a delivered in this medium whilst comparable with 4a delivered in saline/Tween.