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.

Brain metastatic breast cancer is challenging to treat due to the presence of the blood-brain barrier (BBB) and a lack of ability to target precisely. Most drugs fail to cross the BBB limiting their effectiveness. To combat this problem, a brain metastatic breast cancer cell (MDA-MB-831) membrane-coated polymeric nanoparticle (CCNP) was synthesized. The small size (∼70 nm) and anionic surface charge (−20 mV) achieved during formulation allowed for high penetration and retention in the brain when compared to the PEGylated polymeric nanoparticle alone (mPEG-PLGA or NP). Doxorubicin-loaded CCNP showed high preferential cytotoxicity in vitro. Live (4-120 h) and ex vivo near-infrared imaging in nude mice showed extended circulation and retention of CCNP compared to uncoated nanoparticles. These data indicate that drug/dye-loaded CCNPs demonstrate excellent potential for cancer theranostics of brain metastatic breast tumors.

Background Recent studies have shown that low density lipoproteins reconstituted with the natural omega 3 fatty acid docosahexaenoic acid (LDL-DHA) is selectively cytotoxic to liver cancer cells over normal hepatocytes. To date, little is known about the subcellular events which transpire following LDL-DHA treatment. Methods Herein, murine noncancer and cancer liver cells, TIB-73 and TIB-75 respectively, were investigated utilizing confocal microscopy, flow cytometry and viability assays to demonstrate differential actions of LDL-DHA nanoparticles in normal versus malignant cells. Results Our studies first showed that basal levels of oxidative stress are significantly higher in the malignant TIB-75 cells compared to the normal TIB-73 cells. As such, upon entry of LDL-DHA into the malignant TIB-75 cells, DHA is rapidly oxidized precipitating global and lysosomal lipid peroxidation along with increased lysosomal permeability. This leakage of lysosomal contents and lipid peroxidation products trigger subsequent mitochondrial dysfunction and nuclear injury. The cascade of LDL-DHA mediated lipid peroxidation and organelle damage was partially reversed by the administration of the antioxidant, N-acetylcysteine, or the iron-chelator, deferoxamine. LDL-DHA treatment in the normal TIB-73 cells was well tolerated and did not elicit any cell or organelle injury. Conclusion These studies have shown that LDL-DHA is selectively cytotoxic to liver cancer cells and that increased levels of ROS and iron catalyzed reactions promote the peroxidation of DHA which lead to organelle dysfunction and ultimately the demise of the cancer cell. General significance LDL-DHA selectively disrupts lysosomal, mitochondrial and nuclear function in cancer cells as a novel pathway for eliminating cancer cells.