A Review on Metal Complexes and their Anti-Cancer Activities: Recent Advances from In vivo Studies (2017–2023)

Abstract

Transition metal complexes represent a distinct class of anticancer agents that leverage redox activity, coordination versatility, and structural diversity to target cancer through mechanisms often inaccessible to organic drugs. Since the clinical introduction of cisplatin, metal-based complexes have emerged as a cornerstone of cancer chemotherapy, offering diverse mechanisms of action that extend far beyond conventional organic therapeutics. While platinum drugs remain widely used, their clinical utility is often limited by severe systemic toxicity, intrinsic or acquired resistance, and a narrow spectrum of efficacy. Consequently, significant research efforts have focused on alternative metallodrugs based on ruthenium, gold, copper, iridium, and osmium—metals that exploit unique redox, coordination, and photophysical properties to target cancer cells with improved selectivity and novel mechanisms. Despite numerous In vitro studies highlighting the promise of these complexes, only a fraction have demonstrated robust efficacy in In vivo models—essential for bridging the translational gap to clinical application. This review critically evaluates recent advances (2017–2023) in the In vivo antitumor activity of non-platinum and next-generation platinum complexes, with emphasis on tumor growth inhibition (e.g., up to 75% reduction in xenograft mass), survival benefit (e.g., median survival extended from 18 to 27 days in orthotopic glioblastoma), and toxicity profiles in murine and zebrafish models. We highlight structurally innovative agents—such as jatrorrhizine–platinum conjugates, coumarin–ruthenium hybrids, N-heterocyclic carbene–gold complexes, thiosemicarbazone–copper derivatives, and cyclometalated iridium/osmium systems—that overcome cisplatin resistance, induce mitochondrial dysfunction, trigger immunogenic cell death, or enable photodynamic therapy. Special attention is given to complexes that have progressed to clinical trials (e.g., NAMI-A, KP1339, TLD1433, Casiopeínas®) and those exhibiting theranostic potential. By synthesizing In vivo evidence across metal classes, this review underscores the therapeutic viability of metallodrugs beyond platinum, while acknowledging persistent challenges—including inconsistent preclinical methodologies, limited pharmacokinetic data, and poor scalability—that hinder clinical translation. The review advocates for community-wide adoption of standardized In vivo protocols (e.g., uniform animal models, dosing regimens, and efficacy endpoints) to enhance reproducibility and accelerate the development of metallodrugs from bench to bedside.