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SHR Neuro Cancer Cardio Lipid Metab Microb

Mathlouthi, S; Kuryk, L; Rinner, B; Bellio, G; Casagrande, L; Pesce, C; Fragassi, A; Salmaso, S; Mastrotto, F; Garofalo, M.
A 3D coculture model of hepatocellular carcinoma: addressing challenges with glycopolymers re-targeted oncolytic viruses
J DRUG DELIV SCI TEC. 2026; 115: 107658 Doi: 10.1016/j.jddst.2025.107658
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Co-authors Med Uni Graz
Rinner Beate
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Abstract:
Despite recent advancements in cancer treatment, the management and prognosis of hepatocellular carcinoma (HCC) remain poor. Previous two-dimensional (2D) cell culture studies have shown that oncolytic adenoviruses (OVs) coated with a cationic galactosylated polymer (Gal32-b-Agm29) that target the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocyte membranes, can be used for HCC therapy. Although the oncolytic adenovirus Ad5/3-D24-ICOSL incorporates tumor-targeting modifications, its systemic administration still faces challenges such as rapid immune clearance. Coating OVs with Gal32-b-Agm29 addresses these issues by (i) shielding the viral capsid to reduce recognition by neutralizing antibodies (NAbs) and prolong circulation time and (ii) harnessing galactosyl residues to engage ASGPR-mediated uptake, which is more highly expressed in HCC cells than in normal hepatocytes, thereby improving tumor-specific delivery. To further explore the use of Gal32-b-Agm29-coated OVs (PC-OVs) for HCC treatment, we investigated the in vivo safety profile of PC-OVs and their selective oncolytic activity in advanced in vitro models. Confocal microscopy of explanted murine tissues obtained after intravenous injection of PC-OVs into healthy C57BL/6 mice revealed selective liver accumulation, accompanied by low hepatic enzyme levels (ALT and AST), supporting both targeted delivery and biocompatibility. In vitro studies on HepG2 cells preincubated with NAbs revealed that PC-OVs display greater cytotoxicity than uncoated OVs do, along with NAb reduction, suggesting that the polymer coating may protect OVs from immune recognition and clearance. A novel three-dimensional (3D) coculture model of HepG2 spheroids and HLA-matched immune cells, which mimics the tumor microenvironment, confirmed greater PC-OV efficacy in reducing tumor volume and NAb production, highlighting the polymer shielding effect. These findings support the use of targeted polymer coatings to increase OV accumulation in specific tissues and improve therapy.

Find related publications in this database (Keywords)
3D-cell culture model
Oncolytic adenovirus
Hepatocellular carcinoma
Cationic polymers
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