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Correction for 'The side effects of platinum-based chemotherapy drugs: a review for chemists' by Rabbab Oun et al., Dalton Trans., 2018, 47, 6645-6653.

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are regularly prescribed in the treatment of cancer and while they are effective, their use is limited by their severe, dose-limiting side effects (also referred to as adverse effects/events). In total, a cancer patient can experience any combination of around 40 specific side effects. The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression, and for oxaliplatin it is neurotoxicity. Other common side effects include anaphylaxis, cytopenias (including leukopenia and neutropenia, thrombocytopenia, and anaemia), hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, and asthenia. The side effects may require patients to be prescribed dose reductions in their platinum drugs of between 25 and 100%. Furthermore, patients require extensive monitoring of their biochemistries, kidney and liver function, and depending on the drug, hearing tests. Finally, patients are commonly co-prescribed additional non-chemotherapy based drugs to treat the side effects which can include antiemetics, antibiotics and myeloid growth factors, mannitol, propafenone, saline hyperhydration, magnesium supplements, monoclonal antibody cytokine blockers, and antioxidants.

Since its approval in 1979 cisplatin has become one of the most extensively used chemotherapeutics in the clinic and although cell resistance and toxicity hinder its efficacy it continues to be a gold standard regimen. Cisplatin's side effects primarily include nephrotoxicity, gastrointestinal toxicity, neurotoxicity and ototoxicity. Cardiotoxicity is generally not defined as a side effect of cisplatin. However, over the past decade there has been a surge in the amount of clinical cases reporting a vast array of cardio-toxic events occurring during or shortly after cisplatin infusion, these range from angina to cardiac ischemia and chronic heart failure. This review intends to discuss the clinical cardiac manifestations of cisplatin specifically tachycardia and bradycardia which can be lethal and the possible mechanisms of action., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy.

The anticancer drug cisplatin was encapsulated within the cucurbit[7]uril macrocycle to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB[7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit[7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 Å). Whilst CB[7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB[7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB[7] markedly slows tumour growth. The ability of cisplatin@CB[7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB[7] and free cisplatin, the total concentration of circulating cisplatin@CB[7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.

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