Hepatic Arterial Infusion of Low-Density Lipoprotein Docosahexaenoic Acid Nanoparticles Selectively Disrupts Redox Balance in Hepatoma Cells and Reduces Growth of Orthotopic Liver Tumors in Rats

Abstract

Background & Aims Dietary intake of the natural omega-3 fatty acid docosahexaenoic acid (DHA) has been implicated in protecting patients with viral hepatitis B or C from developing hepatocellular carcinoma (HCC). Little is known about the effects of DHA on established solid tumors. Herein, we describe a low-density lipoprotein (LDL)-based nanoparticle that acts as a transporter for unesterified DHA (LDL–DHA) and demonstrates selective cytotoxicity towards HCC cells. We investigated the ability of LDL–DHA to reduce growth of orthotopic hepatomas in rats. Methods ACI rats were given intrahepatic injections of rat hepatoma cells (H4IIE); 24 tumor-bearing rats (mean tumor diameter, ~1 cm) were subject to a single hepatic artery injection of LDL nanoparticles (2 mg/kg) loaded with DHA (LDL–DHA), triolein (LDL–TO) or sham surgery controls. Tumor growth was measured by magnetic resonance imaging and other methods; tumor, liver and serum samples were collected and assessed by histochemical, immunofluorescence, biochemical and immunoblot analyses. Results Three days after administration of LDL–TO or sham surgery, the control rats had large, highly vascularized tumors that contained proliferating cells. However, rats given LDL–DHA had smaller, pale tumors that were devoid of vascular supply and greater than 80% of the tumor tissue was necrotic. Four to 6 days after injection of LDL–DHA, the tumors were 3-fold smaller than those of control rats. The liver tissue that surrounded the tumors showed no histologic or biochemical evidence of injury. Injection of LDL–DHA into the hepatic artery of rats selectively deregulated redox reactions in tumor tissues by: increasing levels of reactive oxygen species and lipid peroxidation, depleting and oxidizing glutathione and nicotinamide adenine dinucleotide phosphate, and significantly downregulating the antioxidant enzyme glutathione peroxidase-4. Remarkably, the redox balance in the surrounding liver was not disrupted. Conclusion LDL–DHA nanoparticle selectively kills hepatoma cells and reduces growth of orthotopic liver tumors in rats. It induces tumor-specific necrosis by selectively disrupting redox balance within the cancer cell.

Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma

“…These findings are in keeping with previous reports on LDL-DHA’s effect on GPX4 in H4IIE. 8 Measurements on GPX4 activity also mirrored the effects seen for GPX4 protein levels, LDL-DHA treatments strikingly curtailed GPX4 activity in all of the HCC cells (Figure 4C). …”

“…7 Transarterial administration of LDL-DHA nanoparticles to a syngeneic rat model of HCC was able to selectively kill hepatoma cells (>80% tumor) in situ, reducing the tumor growth 3 fold compared to control treated rats. 8 The residual LDL-DHA treated tumors were deplete of the reducing equivalents, glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), but contained high *levels of reactive oxygen species (ROS) and lipid peroxidation. Meanwhile the normal liver tissue that surrounded these tumors showed no histologic or biochemical evidence of injury.…”

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…228 Hepatic arterial infusion of LDL-based NPs was employed for docosahexaenoic acid (DHA) transporting. 229 LDL-DHA showed selective cytotoxicity against rat (H4IIE), mouse (Hepa1C7, TIB-75) and human (SK-Hep1) HCC cells, and its hepatic artery injection generated improved therapeutic and biologic effects compared with LDL NPs loaded with triolein or sham surgery controls.…”

Advances in Management of Hepatocellular Carcinoma

“…2, Therefore, there is an unmet need for the development of therapeutic modalities for the management of HCC. In a recent publication in Gastroenterology, Wen et al 3, explored the role of low-density lipoprotein docosahexaenoic acid labeled (LDL-DHA) nanoparticles in the management of HCC in rats. This study was based on the principle of antitumor effect of omega-3-fatty acids in patients with hepatitis B or C infection.…”

“…It induces tumor-specific necrosis by selectively disrupting redox balance within the cancer cell. 3 Mark E. Reeves, 4 Jason Cheng, 3 Roger Grove, 1 and Michael E. de Vera, 3 1 Loma Linda University Medical Center, Department of Radiation Medicine, 2 Department of Diagnostic Radiology, 3 Transplantation Institute and Liver Center, 4 V A Loma Linda Health Care System 11201 Benton Street Loma Linda, CA 92357, USA Objective: This prospective randomized clinical trial was developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC). This report describes results of a planned interim analysis.…”