Abstract 398: NOVO-111: A macrocycle drug conjugate engineered for improved tumor targeting and tolerability.

Abstract Background: NOVO-111 is a novel gadolinium(III) texaphyrin-platinum(IV) complex designed as a tumor-affinic prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate). The texaphyrin moiety confers redox activity and tumor localization properties intended to improve platinum delivery and reduce systemic toxicity. Preclinical data suggest NOVO-111 is not only more effective as an antitumor agent but also better tolerated than oxaliplatin. Methods: Pharmacokinetic (PK), biodistribution, and pharmacodynamic (PD) studies were performed in nude mice bearing HCT-116 colorectal xenografts (KRAS^G13D^). Animals received intravenous oxaliplatin (4 mg/kg, MTD) or equimolar (17 mg/kg) and three-fold higher (50 mg/kg; ≤MTD) doses of NOVO-111. Plasma and tissue samples were analyzed for platinum (Pt) levels and for activation of the p53/p21 pathway by immunoblotting. Results: Following administration, ∼97% of NOVO-111 became plasma bound over 2 hours. A small free Pt fraction (as NOVO-111) decayed slowly (t1/2 = 11.4 h), suggesting prolonged systemic exposure. Compared to oxaliplatin, NOVO-111 produced higher Pt accumulation (1.5-7-fold) in plasma, liver, kidney, heart, ovary, and testes, while tumor and ileum exposure were comparable at equimolar doses. At 50 mg/kg, Pt levels increased ∼3-fold in normal tissues but >5-fold in tumor, consistent with selective texaphyrin-mediated accumulation. In vivo, NOVO-111 achieved greater HCT-116 tumor growth inhibition than an equi-tolerated dose of oxaliplatin, without increased systemic toxicity. Both agents, however, induced comparable tumor p53/p21 upregulation. indicating that PK features resulting in enhanced exposure and sustained Pt(II) release also likely drive NOVO-111’s superior efficacy. Conclusions: NOVO-111 displays unique PK and tumor-targeting characteristics that yield improved therapeutic performance relative to oxaliplatin. Prolonged Pt(II) persistence, enhanced tumor accumulation, and favorable tolerability together support its advancement as a next-generation platinum-based therapeutic for colorectal and other solid tumors. These findings underscore the translational potential of texaphyrin-guided delivery platforms to overcome long-standing limitations of traditional platinum chemotherapy. Citation Format: Jonathan Felipe Aramubla, Guangan He, Gregory Thiabaud, Kathryn Shelton, Luke J. Segura, Jonathan L. Sessler, Rick A. Finch, Zahid H. Siddik. NOVO-111: A macrocycle drug conjugate engineered for improved tumor targeting and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 398.