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.
OBJECTIVE
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. Here we describe a low-density lipoprotein-based nanoparticle that acts as a transporter for unesterified DHA (LDL-DHA) and demonstrates selective cytotoxicity toward HCC cells. We investigated the ability of LDL-DHA to reduce growth of orthotopic hepatomas in rats.


METHODS
AxC-Irish (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 >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 down-regulating the antioxidant enzyme glutathione peroxidase-4. Remarkably, the redox balance in the surrounding liver was not disrupted.


CONCLUSIONS
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.
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Xiaodong
X
Wen
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Lacy
L
Reynolds
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Rohit S
RS
Mulik
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Soo Young
SY
Kim
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Tim
T
Van Treuren
Children's Research Institute, Department of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
Liem H
LH
Nguyen
Children's Research Institute, Department of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
Hao
H
Zhu
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: ian.corbin@utsouthwestern.edu.
Ian R
IR
Corbin
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000378:metabolism; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles; D009336:Necrosis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D000975:Antioxidants; D004337:Drug Carriers; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids
Lipid Peroxidation; Liver Cancer; Nanomedicine; Omega-3 Fatty Acids