Asialoglycoprotein receptor-mediated delivery of copper to hepatic tumors exerted inhibitory effect on tumor growth and progression

Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality and its rising incidence underscores the urgent need to explore novel therapeutic targets. Cancer is often characterized by dysregulated copper metabolism, which plays a crucial role in modulating tumor cell properties like cell proliferation, angiogenesis and metastasis. Therefore, exploiting their metabolic vulnerability using copper overload-based anticancer strategies has emerged as a novel approach. Despite the significant therapeutic potential of copper, its application in anticancer therapy has been limited due to systemic toxicity and non-target localization. In the present study we report targeted delivery of copper to the tumor site and its anticancer therapeutic potential of copper conjugated aminated arabinogalactan (Cu-aAG) in HCC. The synthesized compound was characterized using FT-IR, NMR, Mass spectroscopy and assessed for its anti-cancer therapeutic potential against the Wistar rat model of N-nitrosodiethylamine-induced hepatocellular carcinoma. The chemical characterization of Cu-aAG revealed successful copper complexation as evidenced by characteristic FT-IR peaks and elemental analysis showing 1.19% copper content. The involvement of amine and hydroxyl groups in the complexation was further confirmed by NMR and mass spectral analysis thus ensuring formation of stable, copper-centered co-ordination complexes. Cu-aAG treatment to tumor bearing Wistar rats significantly decreased tumor burden and tumor multiplicity (3.92 ± 2.9) as compared to untreated Tumor group (18.90 ± 3.02). Further, Cu-aAG treatment induced apoptotic cell death, cell cycle arrest, and inhibited angiogenesis. These findings highlight the potential of targeted delivery of copper overload-mediated anticancer therapy for inhibiting tumor growth and progression in HCC.