Naphthalimide-polyamine conjugates: a promising avenue for targeted anticancer therapy

Although chemotherapy is fundamental in cancer therapy, its effectiveness is restricted by systemic toxicity and drug resistance. By combining DNA intercalation, topoisomerase inhibition, and tumor microenvironment modulation, naphthalimide-polyamine conjugates have emerged as promising agents targeting multiple pathways. This review explores how structural innovations in conjugates can overcome therapeutic resistance and minimize off-target effects. In the past, early derivatives such as amonafide encountered clinical challenges because of dose-limiting myelosuppression (e.g., >400 mg/m²). Nonetheless, recent progress in polyamine-mediated targeting and nanocarrier delivery has rejuvenated this class. We present a new Type I-VII classification approach that relates structural modifications—like heterocyclic fusion, polyamine chain adjustments, and substituent effects—to mechanistic outcomes. For example, compounds such as BND-12 inhibit metastasis in hepatocellular carcinoma by 61.8 % through ROS-induced mitochondrial dysfunction, whereas LU-79553 shows sub-micromolar effectiveness (IC₅₀ ≤ 0.32 μM) in colorectal cancer with minimal hematotoxicity. Key advancements include: (1) Triple-action synergy, which simultaneously induces DNA damage through p53/PARP-1, disrupts autophagy regulation, and inhibits VEGF/MMP, thereby interfering with adaptive resistance mechanisms. (2) Targeted delivery: The use of polyamine transporters (PAT) and nanocarriers boosts tumor selectivity, as shown by compound 17, which reduces cisplatin resistance by 2–9 times by depleting lysosomal polyamines. (3) Structure-activity relationship (SAR) design: Adding a chlorine atom at the C₄ position, such as in 4-ClNAHSPD, enhances DNA binding affinity (Kb = 1.7 × 10⁴ M⁻¹) and increases γ-H₂AX foci formation by 1.8 times, while rigid cycloalkanediamine linkers improve cell cycle arrest. Preclinical success has been achieved, yet problems with metabolic stability and neurotoxicity persist. Future research focuses on AI-driven polyamine enhancement, nanoplatforms that can cross the blood-brain barrier (such as Angiopep-2-functionalized Ti@FeAu), and non-apoptotic cell death mechanisms like pyroptosis. Through the integration of structural innovation and multi-mechanistic synergy, this research sets up a design framework for precision oncology, illustrated by AI-optimized polyamine chains and nanoplatforms capable of crossing the blood-brain barrier. These methods provide a practical strategy for future cancer therapies aimed at overcoming adaptive resistance.