Targeted downregulation of MYC mediated by a highly efficient lactobionic acid-based glycoplex to enhance chemosensitivity in human hepatocellular carcinoma cells

Abstract

The chemosensitization of tumor cells by gene therapy represents a promising strategy for hepatocellular carcinoma (HCC) treatment. In this regard, HCC-specific and highly efficient gene delivery nanocarriers are urgently needed. For this purpose, novel lactobionic acid-based gene delivery nanosystems were developed to downregulate c-MYC expression and sensitize tumor cells to low concentration of sorafenib (SF). A library of tailor-made cationic glycopolymers, based on poly(2-aminoethyl methacrylate hydrochloride) (PAMA) and poly(2-lactobionamidoethyl methacrylate) (PLAMA) were synthesized by a straightforward activators regenerated by electron transfer atom transfer radical polymerization. The nanocarriers prepared with PAMA₁₁₄-co-PLAMA₂₀ glycopolymer were the most efficient for gene delivery. These glycoplexes specifically bound to the asialoglycoprotein receptor and were internalized through the clathrin-coated pit endocytic pathway. c-MYC expression was significantly downregulated by MYC short-hairpin RNA (MYC shRNA), resulting in efficient inhibition of tumor cells proliferation and a high levels apoptosis in 2D and 3D HCC-tumor models. Moreover, c-MYC silencing increased the sensitivity of HCC cells to SF (IC₅₀ for MYC shRNA + SF 1.9 μM compared to 6.9 μM for control shRNA + SF). Overall, the data obtained demonstrated the great potential of PAMA₁₁₄-co-PLAMA₂₀/MYC shRNA nanosystems combined with low doses of SF for the treatment of HCC.

Keywords: ARGET ATPR; Asialoglycoprotein receptor-targeted nanosystems; Chemosensitivity; Glycopolymers; Hepatocellular carcinoma; Lactobionic acid-based nanocarriers.