Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for\ud the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and\ud melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and\ud intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered\ud clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing\ud approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual\ud nations. During this time there have been more failures than successes with the development of 14 drugs\ud being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial\ud (satraplatin, picoplatin, LipoplatinTM and ProLindacTM). No new small molecule platinum drug has\ud entered clinical trials since 1999 which is representative of a shift in focus away from drug design and\ud towards drug delivery in the last decade. In this perspective article we update the status of platinum\ud anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued\ud during clinical trials, and discuss the results in the context of where we believe the field will develop over\ud the next decade

Gold nanoparticles (AuNPs) can be used as delivery vehicles for platinum anticancer drugs, improving their targeting and uptake into cells. Here, we examine the appropriateness of different sized AuNPs as components of platinum based drugdelivery systems, investigating their controlled synthesis, reproducibility, consistency of drug loading and stability. The active component of cisplatin was tethered to 25, 55 and 90 nm AuNPs; with the nanoparticles being almost spherical in nature and demonstrating good batch-to-batch reproducibility (24.37 ± 0.62 nm, 55.2 ± 1.75 nm and 89.1 ± 2.32 nm). The size distribution of 25 nm AuNPs has been significantly improved, compared with a previous method which produces polydispersed nanoparticles. Attachment of platinum to the AuNP surface through a polyethylene glycol (PEG) linker exhibits an increase in drug loading with increasing particle size: 25 nm (815 ± 106 drug molecules per AuNP); 55 nm (14,216 ± 880); and 90 nm (54,487 ± 15,996). The stability of the naked, PEGylated and platinum conjugated nanoparticles has been examined over time under various conditions. When stored at 4 ºC there is minimal variation in diameter for all three AuNP sizes; variation after 28 days for the 25 nm AuNPs was 2.4%; 55 nm, 3.3%; and 90 nm, 3.6%. The 25 nm AuNPs also demonstrate minimal changes in UV-visible absorbance over the same time period.

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A series of simple copper N(2)S(2) macrocycles were examined for their potential as biological redox sensors, following previous characterization of their redox potentials and crystal structures. The divalent species were reduced by glutathione or ascorbate at a biologically relevant pH in aqueous buffer. A less efficient reduction was also achieved by vitamin E in DMSO. Oxidation of the corresponding univalent copper species by sodium hypochlorite resulted in only partial (~65 %) recovery of the divalent form. This was concluded to be due to competition between metal oxidation and ligand oxidation, which is believed to contribute to macrocycle demetallation. Electrospray mass spectrometry confirmed that ligand oxidation had occurred. Moreover, the macrocyclic complexes could be demetallated by incubation with EDTA and bovine serum albumin, demonstrating that they would be inappropriate for use in biological systems. The susceptibility to oxidation and demetallation was hypothesized to be due to oxidation of the secondary amines. Consequently these were modified to incorporate additional oxygen donor atoms. This modification led to greater resistance to demetallation and ligand oxidation, providing a better platform for further development of copper macrocycles as redox sensors for use in biological systems.

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