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.

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. 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. 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-mediated delivery of docosahexaenoic acid selectively kills murine liver cancer cells.

AIM: The natural omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), has recently been credited for possessing anticancer properties. Herein, we investigate the cytotoxic actions of DHA-loaded low-density lipoprotein (LDL) nanoparticles in normal and liver cancer cells. MATERIALS & METHODS: LDL-DHA nanoparticles were prepared and subjected to extensive biophysical characterization. The therapeutic utility of LDL-DHA nanoparticles was evaluated in normal and malignant murine hepatocyte cell lines, TIB-73 and TIB-75, respectively. RESULTS & DISCUSSION: The engineered LDL-DHA nanoparticles possessed enhanced physical and oxidative stabilities over native LDL and free DHA. Dose-response studies showed that therapeutic doses of LDL-DHA nanoparticles that completely killed TIB-75 were innocuous to TIB-73. The selective induction of lipid peroxidation and reactive oxygen species in the cancer cells was shown to play a central role in LDL-DHA nanoparticle-mediated cytotoxicity. CONCLUSION: In summary, these findings indicate that LDL-DHA nanoparticles show great promise as a selective anticancer agent against hepatocellular carcinoma.

ApoE3 mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin: study of enhanced activity of curcumin against beta amyloid induced cytotoxicity using in vitro cell culture model.

Beta amyloid plays a main role in the pathophysiology of Alzheimer's disease by inducing oxidative stress in the brain. Curcumin, a natural antioxidant, is known to inhibit beta amyloid and beta amyloid induced oxidative stress. However, low bioavailability and photodegradation are the major concerns for the use of curcumin. In the present study, we have formulated apolipoprotein E3 mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin (ApoE3-C-PBCA) to provide photostability and enhanced cell uptake of curcumin by targeting. Prepared nanoparticles were characterized for particle size, zeta potential, entrapment efficiency and in vitro drug release. The entrapment of curcumin inside the nanoparticles was confirmed by X-ray diffraction analysis. Physicochemical characterization confirmed the suitability of the method of preparation. The photostability of curcumin was increased significantly in nanoparticles compared to plain curcumin. In vitro cell culture study showed enhanced therapeutic efficacy of ApoE3-C-PBCA against beta amyloid induced cytotoxicity in SH-SY5Y neuroblastoma cells compared to plain curcumin solution. Beta amyloid is known to induce apoptosis in neuronal cells, therefore antiapoptotic activity of curcumin was studied using flow cytometry assays. From all the experiments, it was found that the activity of curcumin was enhanced with ApoE3-C-PBCA compared to plain curcumin solution suggesting enhanced cell uptake and a sustained drug release effect. The synergistic effect of ApoE3 and curcumin was also studied, since ApoE3 also possesses both antioxidant and antiamyloidogenic activity. It was found that ApoE3 did indeed have activity against beta amyloid induced cytotoxicity along with curcumin. Hence, ApoE3-C-PBCA offers great advantage in the treatment of beta amyloid induced cytotoxicity in Alzheimer's disease.