Trojan horse tactics: Naphthalimide polyamine conjugates revolutionize cancer treatment

Naphthalimide polyamine conjugates (NPCs) represent a disruptive advance in anticancer drug development by employing multi-target strategies to overcome the limitations of traditional DNA intercalators. Unlike conventional naphthalimide drugs such as Amonafide, which show limited tumor inhibition (46.91 %) and significant toxicity, NPCs leverage the polyamine transporter (PAT) system for selective tumor accumulation-a 'Trojan horse' effect. This review highlights three key advances: (1) optimizing polyamine chain length and aromatic ring substitution (e.g., 3-nitro) to improve PAT affinity and DNA intercalation; (2) adopting multimodal mechanisms, including interference with polyamine metabolism via the SSAT/PAO pathway, leading to autophagy, EMT prevention, and DNA damage; and (3) developing PAT-mediated targeting and nanocarrier systems to enhance solid tumor penetration. Critically, the compelling in vivo efficacy of several lead NPCs, such as conjugate 5b, which achieved >75 % inhibition of tumor growth and metastasis in HCC models, provides a solid foundation for this drug class. Innovations like dual-target conjugates (e.g., flavone-naphthalimide-polyamine) and computational modeling of drug-likeness and binding modes are emerging as promising tools for personalized oncology. Despite facing challenges in synthetic complexity and clinical translation, NPCs hold potential to address key clinical hurdles-poor pharmacokinetics, tumor penetration, and drug resistance-offering a breakthrough strategy for invasive and metastatic cancers.