Profiling the Preclinical Pharmacokinetics and Biodistribution of a Platinum(IV)-Based Oxaliplatin Prodrug OxaliTEX and Their Significance to Antitumor Response

Authors

Guangan He
Gregory D Thiabaud
Kathryn A Shelton
Luke J Segura
Jonathan F Arambula
Jonathan L Sessler
Rick A Finch
Zahid H Siddik

Language

English

Publication Date

12-1-2025

Journal

Molecular Pharmaceutics Journal

DOI

10.1021/acs.molpharmaceut.5c01187

PMID

41160639

PMCID

PMC12974947

PubMedCentral® Posted Date

3-11-2026

PubMedCentral® Full Text Version

Author MSS

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 KRASG13D 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.

Keywords

Animals, Oxaliplatin, Prodrugs, Mice, Humans, Tissue Distribution, Antineoplastic Agents, Mice, Nude, Xenograft Model Antitumor Assays, Female, HCT116 Cells, Organoplatinum Compounds, Male, Platinum, Tumor Suppressor Protein p53, platinum complexes, pharmacokinetics, tissue distribution, gender difference, antitumor response

Published Open-Access

yes

Recommended Citation

He, Guangan; Thiabaud, Gregory D; Shelton, Kathryn A; et al., "Profiling the Preclinical Pharmacokinetics and Biodistribution of a Platinum(IV)-Based Oxaliplatin Prodrug OxaliTEX and Their Significance to Antitumor Response" (2025). Faculty, Staff and Student Publications. 6533.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6533