Development of Ir-cR8-albumin nanomedicine toward the interventional treatment of liver cancer

Abstract

Hepatocellular carcinoma is one of the most challenging malignancies with high incidence and mortality rates in the world. Digital subtraction angiography (DSA)-guided hepatic arterial infusion of the standard chemotherapeutic agent oxaliplatin has the advantages of both precision and efficacy, making it an important therapeutic strategy for advanced-stage liver cancer. However, patients undergoing this treatment still face severe systemic toxicity and poor tolerability of oxaliplatin. In this study, we compared oxaliplatin with a novel albumin nanoparticle-formulated oncolytic peptide Ir-cR8 (Ir-cR8-BSA-NP) in the treatment of orthotropic liver cancers in a mouse model by intravenous injection and in a rabbit model by DSA-guided hepatic arterial infusion. The oncolytic peptide Ir-cR8, containing a cationic octa-arginine ring and a hydrophobic domain, was found to interact with bovine serum albumin and further assemble into spherical nanoparticles with an average diameter of 150 nm. Such albumin opsonisation significantly increases the stability of the peptide and reduces its haemolytic toxicity. In vivo experiments in mice showed that intravenous administration of Ir-cR8-BSA-NP had excellent inhibitory effects on H22 orthotopic liver tumours and reduced toxicity in the animals than oxaliplatin. Furthermore, in the rabbit VX2 orthotopic liver cancer model, oxaliplatin or Ir-cR8-BSA-NP was administered by hepatic artery infusion under DSA guidance, followed by PET/CT assessment of treatment efficacy. The results showed that Ir-cR8-BSA-NP significantly outperformed oxaliplatin in reducing tumour size. Thus, this study demonstrated the combined advantages of a novel membrane-active oncolytic peptide nanomedicine and precise drug delivery enabled by arterial infusion technology for the interventional treatment of liver cancer.