Platinum(IV) prodrugs of the [Pt(P_L)(A_L)(COXi)(OH)]²⁺ type scaffold (where P_L is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A_L is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, 4, exhibited a GI₅₀ of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that 1 and 2 inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs 1–4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity.

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO₃)₂, (2) exhibiting the lowest GI₅₀ of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO₃)₂, (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO₃)₂, (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1–4; however, this was not always translated to the observed cytotoxicity.

This study investigates the chemotherapeutic potential of PtII5CLSS and PtIV5CLSS against breast cancer in vivo. Cell viability was assessed 72 h post-treatment, revealing potent cytotoxic activity with IC50 values of 0.447 μM for PtII5CLSS and 0.922 μM for PtIV5CLSS. Cellular uptake studies used ICP-MS to confirm active transport of both complexes into cells, showing significant accumulation in the nuclear/cytoskeletal fractions. A 28-day toxicity study in female Sprague-Dawley rats demonstrated that escalating doses up to 15 mg/kg (PtII5CLSS) and 30 mg/kg (PtIV5CLSS) caused no mortality nor adverse effects on liver and kidney function. In a chemically induced breast cancer rat model, both complexes significantly reduced tumor weight by 93–100% at doses of 1 and 5 mg/kg, with no observable nephrotoxicity or hepatotoxicity. Histopathological analysis confirmed the reduction or absence of tumors in the majority of the treated animals with PtIV5CLSS (1 mg/kg bw) being the most effective. Toxicity evaluation in sus scrofa pigs showed that PtIV5CLSS was well tolerated at both 1- and 2.5 mg/kg bw, with no mortality, behavioral changes, or signs of acute toxicity. Overall, both PtII5CLSS and PtIV5CLSS demonstrate strong antineoplastic activity against breast cancer with a favorable safety profile, supporting their potential as alternative platinum-based chemotherapeutic agents.