Abstract
OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. It was designed as a prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate) tethered to a tumor-affinic texaphyrin moiety to improve drug delivery to the tumor. However, oxaliTEX was not only more effective as an antitumor agent but also better tolerated in mice. To appreciate this higher therapeutic index and advance its preclinical development, studies were undertaken to profile its plasma pharmacokinetics, distribution to tumor and normal tissues, and pharmacodynamics of the p53/p21 molecular pathway. Nude mice, with or without a subcutaneous colorectal HCT-116 xenograft harboring a phenotypically aggressive KRAS(G13D) mutation, received intravenously a maximally tolerated dose (MTD) of oxaliplatin (4 mg/kg) or an equimolar (17 mg/kg) or 3-fold higher dose (50 mg/kg; ≤MTD) of oxaliTEX and tissue samples were harvested for platinum (Pt) and immunoblot analyses. The Pt from oxaliTEX was rapidly reduced to the activated Pt(II) state, and ∼97% of the total Pt was irreversibly bound to plasma proteins by 2 h. However, a small fraction representing free (unbound) Pt in plasma decayed slowly with a half-life of 11.4 h. Distribution studies consistently identified higher levels of Pt (1.5- to ∼7-fold) with oxaliTEX (17 mg/kg) in plasma, liver, kidney, heart, ovary and testes than with an equimolar dose of oxaliplatin, whereas the difference in the tumor and ileum was negligible. Thus, the reactive Pt(II) species resulting from oxaliTEX do not necessarily arise from oxaliplatin as the anticipated intermediate product. With the oxaliTEX dose approaching the MTD (50 mg/kg), the expected 3-fold increase in Pt levels was observed in the ileum, but Pt levels in the tumor increased >5-fold. This disproportionate increase in tumor levels is consistent with the design of oxaliTEX that induced greater growth inhibition of the HCT-116 xenograft than an equi-tolerated dose of oxaliplatin. However, the p53/p21 pathway as a pharmacodynamic biomarker was upregulated to a similar level in the tumor with both drugs at the MTDs. This suggests that other factors, such as the slow plasma terminal phase of the free Pt(II) species from oxaliTEX that prolongs exposure to low drug concentrations, may contribute to the favorable in vivo antitumor activity and therapeutic index of the conjugate. These characteristics demonstrate superiority of oxaliTEX and generate much optimism for its success in future clinical trials.