Abstract 1073: Preclinical tissue biodistribution and plasma pharmacokinetic studies with oxaliTEX, a novel platinum(IV)-based oxaliplatin prodrug

Abstract

Abstract Purpose: OxaliTEX is a texaphyrin-platinum(IV) prodrug with the ability to deliver the oxaliplatin payload to cisplatin-resistant tumor cells and restore wild-type p53 activation. As a result, the conjugate overcomes both multifactorial mechanisms of cisplatin resistance and transport-defective mechanism of oxaliplatin resistance. In an effort to prepare for translational studies, we have explored its distribution and pharmacokinetics (PK) in mice. Experimental Procedures: Athymic male and/or female nude mice (3-4/group), with or without subcutaneously implanted (flank) HCT-116 colon xenograft, received oxaliplatin (4 mg/kg) and an equimolar (17 mg/kg) or a similar therapeutic (50 mg/kg) dose of oxaliTEX iv. After 24 hours, mice were exsanguinated under anesthesia and plasma and tissues isolated. A separate group of female mice received oxaliTEX (50 mg/kg) and blood was taken at multiple times over the next 24 hours, plasma isolated and samples denatured to prepare protein-free supernatant (PFS) representing “free” platinum. Samples were analyzed for platinum (Pt) by flameless atomic absorption spectrophotometry. Results: At equimolar doses, gross sex differences in plasma or tissue concentrations were not observed for either drug. However, plasma Pt levels with oxaliTEX (0.6-0.7 ng Pt/ml) were 7-fold greater than with oxaliplatin (0.08-0.1 ng/ml). Similarly, a 3-fold greater concentration was also noted in liver (~1.4 vs. ~0.4 ng/mg) and heart (~0.5 vs. ~0.15 ng/mg) from mice treated with the prodrug. Tissues with ≤2-fold differences between the drugs in Pt levels were testes, kidney, ovary, lung, ileum and spleen, with undetectable levels in brain. In female mice bearing HCT-116 xenografts, the general tissue distribution pattern of each drug at the therapeutic dose was unchanged and demonstrated that increasing the oxaliTEX dose resulted in proportionate increase in tissue Pt levels. Notably, tumor Pt levels were ~5-fold greater with the conjugate (oxaliTEX, 1.1 ng Pt/mg; oxaliplatin, 0.21 ng/mg). PK analysis revealed that Pt in plasma and PFS was detectable for the entire 24 hr period and decayed in a biphasic manner, with respective α-phase half-life of 0.07 and 0.2 hr and β-phase half-life of 27 and 11 hr. The AUC in plasma and PFS was 172 and 3.7 μg.hr/ml, respectively. Conclusions: Results suggest that oxaliTEX is sequestered in the plasma by protein binding, leaving low-level systemic exposure to “free” non-protein bound Pt. Since the tissue levels are greater than oxaliplatin at equimolar and/or therapeutic doses in specific organs, this suggests that the low level exposure to “free” Pt contributes to drug tolerance of normal tissues, whereas the tumor-targeting design feature contributes to greater tumor uptake that enhances antitumor effects. Funding was provided by Cancer Prevention and Research Institute of Texas Citation Format: Guangan He, Gregory Thiabaud, Kathyrin A. Shelton, Luke J. Segura, Jonathan L. Sessler, Rick A. Finch, Zahid H. Siddik, Jonathan F. Arambula. Preclinical tissue biodistribution and plasma pharmacokinetic studies with oxaliTEX, a novel platinum(IV)-based oxaliplatin prodrug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1073.