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Kiteplatin, [PtCl 2 ( cis -1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans -1 R ,2 R -DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis , trans , cis -[PtCl 2 (OBz) 2 ( cis -1,4-DACH)] ( 1 ; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·10 6 LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.

Here, polyethylene glycol (PEG)-stabilized solid lipid nanoparticles (SLNs) containing Pt(IV) prodrugs derived from kiteplatin were designed and proposed as novel nanoformulations potentially useful for the treatment of glioblastoma multiforme. Four different Pt(IV) prodrugs were synthesized, starting from kiteplatin by the addition of two carboxylate ligands with different length of the alkyl chains and lipophilicity degree, and embedded in the core of PEG-stabilized SLNs composed of cetyl palmitate. The SLNs were extensively characterized by complementary optical and morphological techniques. The results proved the formation of SLNs characterized by average size under 100 nm and dependence of drug encapsulation efficiency on the lipophilicity degree of the tested Pt(IV) prodrugs. A monolayer of immortalized human cerebral microvascular endothelial cells (hCMEC/D3) was used as in vitro model of blood-brain barrier (BBB) to evaluate the ability of the SLNs to penetrate the BBB. For this purpose, optical traceable SLNs were achieved by co-incorporation of Pt(IV) prodrugs and luminescent carbon dots (C-Dots) in the SLNs. Finally, an in vitro study was performed by using a human glioblastoma cell line (U87), to investigate on the antitumor efficiency of the SLNs and on their improved ability to be cell internalized respect to the free Pt(IV) prodrugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans -1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC 50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5-8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells.

Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl₂( cis -1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds ( cis , trans , cis -[Pt(CBDCA)(ALA)₂( cis -1,4-DACH)], 2 , and cis , trans , cis -[PtCl₂(ALA)₂( cis -1,4-DACH)], 3 ), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters.

With the aim to obtain dual acting drugs able to target both nuclear DNA and mitochondria, Pt(iv) kiteplatin derivatives having dichloroacetate (DCA) ligands in axial positions have been synthesized. The rather fast hydrolysis (t1/2 of ca. 1 h) and reduction (by ascorbic acid) of these Pt(iv) derivatives did not impede a potent pharmacological effect on tumor cells. Moreover, similarly to kiteplatin, also the Pt(iv)-DCA compounds proved to be capable of overcoming oxaliplatin-resistance, which is particularly important in view of the fact that metastatic colorectal cancer is the third most common cancer in males and the second in females. The possible role of DCA released by the Pt(iv) compounds in eliciting the antiproliferative activity has also been investigated. Pt(iv)-DCA compounds determine a substantial increase of ROS production, blockage of oxidative phosphorylation, hypopolarization of the mitochondrial membrane, and caspase-3/7 mediated apoptotic cell death.

Biodegradable, PEG-coated, nanoparticles (NPs) have gained therapeutic application as injectable colloidal systems for the controlled and site-specific release of drugs. In this paper, encapsulation in PLGA-PEG polymer NPs has been exploited to lower the toxicity and to increase the antitumor activity of kiteplatin ([PtCl2(cis-1,4-DACH)]). Kiteplatin contains an isomeric form of the diamine ligand present in oxaliplatin and proved to be particularly active against ovarian and colon cancers. To favor encapsulation of the platinum drug in the hydrophobic core of the polymeric micelles, Pt(iv) prodrugs having hydrophobic carboxylic ligands at the axial positions were used in place of hydrophilic Pt(ii) complexes (compounds 1-4). The size, size distribution, and zeta potential (ZP) were measured by dynamic light scattering (DLS) and laser Doppler velocimetry (LDV), and drug encapsulation efficiency (EE) correlated to the alkyl chain length of the different Pt(iv) prodrugs. The number of the Pt atoms per NP (in the range of 1.3-2.4 × 10(6)) is comparable to that of polysilsesquioxane-based NPs and higher than that found for other nanoparticle platforms. The platinum-loaded PLGA-PEG NPs, tested in vivo in a syngeneic murine solid tumor (LLC), had a higher antitumor effect and, most importantly, were markedly less toxic than kiteplatin.

Kiteplatin, the neglected drug analogous of cisplatin but containing cis-1,4-DACH in place of the two ammines, has been recently reevaluated for its activity against cisplatin- and oxaliplatin-resistant tumors, in particular colo-rectal cancer. With the aim of further improving the pharmacological activity of this drug, Pt(IV) prodrugs were derived by addition of two, differently substituted, benzoate groups in axial positions (X-ray structure). The cytotoxic activity of both compounds resulted markedly potentiated reaching nanomolar concentration against a wide panel of human cancer cells. The ability of benzoate ligands to enhance the activity of kiteplatin most likely originates from their lipophilicity promoting a higher drug accumulation in cancer cells; however, it is to be noted that the increase in pharmacological effect is far greater than the increase in cellular uptake. Overcoming cisplatin- and oxaliplatin-resistance by kiteplatin derivatives appears to relate to the inability of membrane extrusion pumps to remove active Pt species from tumor cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The present review focuses on the "drug targeting and delivery" approach of the selective transportation of cisplatin to bone tumors and bone metastases. This aim is realized by binding cisplatin to (bis)phosphonate ligands or their derivatives. Geminal bisphosphonates are in clinical use in the treatment of several bone-related diseases because of their high affinity for calcium ions and hence for bones. Platinum-bisphosphonate complexes may be easily loaded onto calcium-containing inorganic matrices, such as calcium-doped sol-gel derived silica xerogels and hydroxyapatite nanocrystals, for local administration at the site of the bone malignancy. The composites may be used as bone-filler materials that, in addition to their action as bone substitutes, can also act as controlled platinum-drug releasing agents. The release kinetics of the drug can be tailored for specific therapeutic applications modulating the physico-chemical features of the inorganic matrices. Moreover, apatite nanocrystals loaded with platinum-bisphosphonate prodrugs can be used as injectable material for nanomedical applications (e.g. intracellular drug delivery)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

For over 30 years cisplatin has been one of the most active antitumour agents in clinical use, nevertheless research for overcoming cisplatin toxicity and resistance or for improving its efficacy has never ceased. In this context we have recently proposed dinuclear Pt complexes with bridging geminal bisphosphonates as novel Pt-prodrugs with potential activity at the bone surface after embedment in inorganic matrices and implantation at the tumour site. In the present paper we report the synthesis and full characterization of four new platinum complexes having a dinuclear structure with a bisphosphonate (2-ammonium-1-hydroxyethane-1,1-diyl-bisphosphonate or 3-ammonium-1-hydroxypropane-1,1-diyl-bisphosphonate, AHBP-H and PAM-H, respectively) acting as a bridging ligand between two platinum moieties (cis-[Pt(NH(3))(2)](2+), directly related to cisplatin, and [Pt(cis-1,4-DACH)](2+), known to be able to overcome the cisplatin resistance). Moreover, as a preliminary investigation, the in vitro cytotoxicity of the new complexes has been evaluated on a panel of 13 human tumour cell lines including cisplatin- and multidrug-resistant sublines.