The state-of-play and future of platinum drugs

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   Figure 1

   The structures of the approved platin drugs, showing the carrier a(m)mine ligands in red and the labile chloride or carboxylate-based ligands in green. All platins act as prodrugs, requiring replacement of their labile ligands with water before they are able to bind and disrupt the function of DNA.
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   Figure 2

   The chemical structures of the platin drugs under preclinical and clinical development. For dicycloplatin, the original carboplatin drug molecule is indicated in blue with the additional carboxylate-stabilising ligand shown in green. The hydrogen bonds of dicycloplatin that hold the free ligand to the drug are shown as dashed lines. Also shown is the active component of LA-12 after the loss of its axial ligands (shown in red) when it is reduced from platinum(IV) to platinum(II) within cancer cells. A * indicates a chiral centre: either R or S. Counter ions for phenanthriplatin are not shown but are potentially chloride or nitrate.
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   Figure 3

   The basic chemical structures of the unfunctionalised macrocycle families that have shown potential as drug delivery vehicles for platins. The n denotes the number of subunits that make up the macrocycles; six to eight for cucurbiturils and cyclodextrins and four for p-sulfonatocalixarene. For calix[n]arenes, R can be a variety of groups, but for drug delivery it is typically an anionic SO₃ group.
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   Figure 4

   The structure of the platin polymer formulation, ProLindac, that yields the same active component as oxaliplatin (shown in red) in the low pH environment of cancer cells.
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   Figure 5

   A schematic diagram showing a unique method of attaching a platin drug to the surface of gold nanoparticles. Cyclodextrin macrocycles (red), which have been modified with thiol-groups on the minor portal, form a monolayer on the surface of the gold (yellow). The platin drug is held to the cyclodextrin through an adamantine ligand (black). Upon entering the cells, the platin is reduced from platinum(IV) to platinum(II), thus releasing cisplatin (green).
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   Figure 6

   The four methods of attachment of platin drugs (red) to carbon nanotubes showing (A) cisplatin encapsulation within the cavity, (B) coordination to surface carboxylate groups, (C) coordination to surface amine groups through the formation of a peptide bond (blue) and (D) through a tether that holds the platin to the surface of the carbon nanotube through hydrophobic effects (green).
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   Figure 7

   Examples of two complexes where a platin drug has been coordinated to an essential nutrient to increase the selectivity of the platinum for cancer cells showing (A) the active component of cisplatin (red) attached to folic acid and (B) the use of chemically modified estradiol to permanently incorporate a cisplatin-like drug (green) into its structure, where x=2, 4, 6 or 8 and y=1 or 2.

• © 2015 Society for Endocrinology