Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application

Abstract

Platinum(IV) complexes are promising candidates as prodrugs for oral application in anticancer chemotherapy. However, only a few Pt(IV) compounds entered (pre)clinical trials, e.g. satraplatin, while most of the others were only tested in vitro. Aim of the study was investigation of the in vivo pharmacological behavior as well as the anticancer activity of two novel platinum(IV) complexes vs. satraplatin. The drugs were selected due to significantly different in vitro cytotoxicity while sharing some physicochemical properties (e.g. lipophilicity). Initial experiments indicated that the highly in vitro cytotoxic compound 1 ((OC-6-33)-dichloridobis((4-ethoxy)-4-oxobutanoato)-bis(ethylamine)platinum(IV)) was also characterized by high drug absorption and tissue platinum levels after oral application. Interestingly, analysis of serum samples using SEC-ICP-MS revealed that the administered drugs have completely been metabolized and/or bound to proteins in serum within 2 h after treatment. With regard to the activity in vivo, the outcomes were rather unexpected: although potent anticancer effect of 1 was observed in cell culture, the effects in vivo were rather minor. Nevertheless, 1 was superior to 2 ((OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)-bis((4-cyclopentylamino)-4-oxobutanoato)platinum(IV)) after i.p. administration, which was, at least to some extent, in accordance to the cell culture experiments. After oral gavage, both compounds exhibited comparable activity. This is remarkable considering the distinctly lower activity of 2 in cell culture as well as the low platinum levels detected both in serum and tissues after oral application. Consequently, our data indicate that the prediction of in vivo anticancer activity by cell culture experiments is not trivial, especially for orally applied drugs.

Fig. 1

General formula of diam(m)inebis-, tris- and tetrakis(carboxylato)platinum(IV) complexes developed, in our group (DACH 1R,2R-diaminocyclohexane, CBDCA 1,1-cyclobutanedicarboxylate, mal malonate, ox oxalate, glyc glycolate)

Fig. 2

Structural formulas of the platinum(IV) complexes under investigation

Fig. 3

Total platinum levels of compound 1, 2 and satraplatin in mice organs, blood pellet and serum 2 h after single dose oral application (40 mg/kg), corresponding to Pt doses of 12.1, 10.32 and 15.63 mg/kg, respectively

Fig. 4

In vivo anticancer activity of compound 1, 2 and satraplatin. CT-26 cells were injected subcutaneously into the right flank of BALB/c mice. Mice were treated on day 4, 7, 11, and 14 (indicated by black triangles) with either compound 1 at concentrations of 8.5 mg/kg (i.p.), 34.1 mg/kg (p.o.) and 51.7 mg/kg (p.o.), compound 2 at concentrations of 10 mg/kg (i.p.) and 40 mg/kg (p.o.) or satraplatin at 40 mg/kg (p.o.). Data visualized in the same color correspond to equimolar concentrations. a Tumor volumes were calculated as described in the “Experimental” part. Each experimental group contained four animals. Data are mean ± SEM. b Animals were sacrificed on day 15 and tumors were collected and weighed. Data are expressed as fold change to the untreated control group of the respective experiment

Fig. 5

Platinum accumulation after multiple dose administration (i.p. and p.o.) of complex 1 (a) and complex 2 (b) in different tissues, blood pellet and serum originating from CT-26-bearing mice. Data are based on four animals per group, average concentrations and corresponding standard deviations are given