Synthesis and characterization of cyclohexane-1R,2R-diamine-based Pt(iv) dicarboxylato anticancer prodrugs: their selective activity against human colon cancer cell lines.

Three pairs of asymmetric dicarboxylato derivatives based on the cisplatin and oxaliplatin-like skeletons have been synthesized de novo or re-synthesized. The axial ligands consist of one medium-chain fatty acid (MCFA), namely clofibrate (i.e. 2-(p-chlorophenoxy)-2-methylpropionic acid, CA), heptanoate (HA) or octanoate (OA), respectively, and an inactive acetato ligand that imparts acceptable water solubility to such conjugates. Stability tests provided evidence for the partial formation of two hydrolyzed products, corresponding to two monoaqua diastereomers derived from the substitution of an equatorial chlorido ligand with a water molecule. The complexes have been tested on three different colon cancer cell lines having different histological history, and also on the cisplatin-sensitive A2780 ovarian cancer cell line for comparison. This allowed the evaluation not only of the increase in activity on passing from Pt(ii) to Pt(iv) derivatives, but also the selectivity towards colon cancer cells brought about by the cyclohexane-1R,2R-diamine carrier ligand.

Cisplatin and valproate released from the bifunctional [Pt(IV)Cl2(NH3)2(valproato)2] antitumor prodrug or from liposome formulations: who does what?

The cisplatin-sensitive human ovarian cancer cells A2780 have been challenged with cationic liposomes containing the single drug cisplatin or valproate or their combination with an approximate 1 : 2 molar ratio, i.e. the same ratio present in preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv), that releases such metabolites by intracellular Pt(iv) → Pt(ii) reduction. The results of this comparison confirm that valproate barely penetrates cells unless it is transported by liposomes or it is coordinated to a lipophilic Pt(iv) assembly. The two drugs have a synergistic action, cisplatin being the more potent antiproliferative agent. Even if the preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv) releases cisplatin and valproate in the same amount as the liposome formulation, the Pt(iv) derivative is more active. This important feature, common to all Pt(iv) complexes having very lipophilic carboxylates, is attributable to their propensity to remain in cells and to continuously bind DNA, unlike cisplatin that is partially removed from cells by efficient efflux pathways.

Functionalized nonporous silica nanoparticles as carriers for Pt(iv) anticancer prodrugs.

Nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups were proposed as potential delivery systems for Pt(iv) antitumor prodrugs. Spherical SNPs containing two different external arms, i.e. 3-aminopropyl and N-(6-aminohexyl)aminomethylene, of around 125 nm hydrodynamic diameter were loaded with two different cisplatin-based Pt(iv) complexes, namely (OC-6-44)-diamminedichloridoethoxidosuccinatoplatinum(iv) and (OC-6-44)-diamminedichloridoacetylamidosuccinatoplatinum(iv), through the formation of amide bonds between the pendant amino groups on SNPs and the free carboxylic group of the complexes. In the presence of the N-(6-aminohexyl)aminomethylene arm, the Pt(iv)-SNP conjugates showed a negligible (unwanted) Pt release by hydrolysis, whereas in the presence of ascorbic acid the reduction of Pt(iv) → Pt(ii) caused the substantial release of the active metabolite cisplatin. Conjugate Pt(iv)-SNP exhibited better antiproliferative activity on the Pt-sensitive A2780 human ovarian cancer cell line than the parent cisplatin and their free Pt(iv) precursors, due to their more efficient cellular uptake, likely by endocytosis.