Low Density Lipoprotein Function Research Articles

Low density lipoprotein receptor (LDLR)-targeted lipid nanoparticles for the delivery of sorafenib and Dihydroartemisinin in liver cancers

AimsLiver cancer is one of the leading causes of cancer mortality worldwide. Inspired by the biological structure and function of low-density lipoprotein (LDL), in this study, an ApopB-100 based targeted lipid nanoparticles was synthesized to improve the therapeutic efficacy in liver cancer treatment. Main methodsThe biological composition of ApopB is similar to LDL which can effectively increase the targeting efficiency of nanoparticles in LDL receptor (LDLR)-overexpressed liver tumors. KeyfindingsWe have demonstrated that the co-administration of sorafenib (SRF) and Dihydroartemisinin (DHA) could exhibit synergistic anticancer effect in HepG2 liver cancer cells. DHA produced excessive cellular reactive oxygen species (ROS) and induced greater apoptosis of cancer cells. LDL-based SRF/DHA-loaded lipid nanoparticles (LD-SDN) showed remarkable decrease in the cell viability compared to that of either of single drug treated cancer cells. Combination of SRF+DHA resulted in predominant SubG1 proportion of cells. LD-SDN exhibited the highest SubG1 (%) of cells compared to that of any of the individual drugs. Most importantly, robust antitumor response and delayed tumor growth was observed for LD-SDN treated xenograft tumor model. Ki67 proliferation index of LD-SDN (22.1 ± 5.6%) is significantly lesser compared to that of either control (86.2 ± 6.9%) or SRF (75.4 ± 4.89%) or DHA (69.4 ± 6.9%). SignificancesThese data provide strong evidence that LDL-mimetic lipid nanoformulations could be utilized as a biocompatible and tumor targeted platform for the delivery of multiple anticancer drugs in cancer treatment.

Low density lipoprotein-inspired nanostructured lipid nanoparticles containing pro-doxorubicin to enhance tumor-targeted therapeutic efficiency

Inefficient tumor accumulation and controlling drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. Inspired by the biological structure and function of low-density lipoprotein (LDL), a pH-sensitive ApoB-100/Oleic acid-DOX/NLC (AODN) nanoparticle based on nanostructured lipid carrier (NLC) was prepared in this study. The biological composition of ApoB-containing NLC nanoparticles is similar to that of LDL, which can effectively increase the cycle time and targeting efficiency of nanoparticles. Meantime, the doxorubicin prodrug strategy was used to increase the drug loading of the nanoparticles and achieve drug-sensitive release. In vitro results indicated that AODN nanoparticles can cause more drugs to be phagocytosed by LDL receptor-mediated endocytosis, thus showing high cytotoxicity in 4T1 cells. In vivo experiments have shown that pH-sensitive AODN nanoparticles can cause more drugs to accumulate in the tumor site, reducing systemic toxicity and effectively inhibiting orthotopic breast cancer. These data provide strong evidence that the strategy of combining bionics and prodrug technology provides a new approach to improving the efficiency of chemotherapy drugs in cancer treatment. Statement of SignificanceInefficient tumor accumulation and controlling drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. Inspired by low density lipoprotein, a pH-sensitive ApoB-100/oleic acid-DOX/NLC (AODN) nanoparticle based on nanostructured lipid carrier (NLC) was prepared. Its biological composition is similar to that of LDL, which can effectively increase the cycle time and targeting efficiency of drugs. Then, the doxorubicin prodrug strategy was used to increase the drug loading of the nanoparticles and achieve drug-sensitive release. AODN nanoparticles can effectively inhibit tumor by effectively accumulating at tumor site and controlling release. The strategy of combining bionics and prodrug technology provides a new approach to improving the efficiency of chemotherapy drugs in cancer treatment.

PFOS induced lipid metabolism disturbances in BALB/c mice through inhibition of low density lipoproteins excretion

Male BALB/c mice fed with either a regular or high fat diet were exposed to 0, 5 or 20 mg/kg perfluorooctane sulfonate (PFOS) for 14 days. Increased body weight, serum glucose, cholesterol and lipoprotein levels were observed in mice given a high fat diet. However, all PFOS-treated mice got reduced levels of serum lipid and lipoprotein. Decreasing liver glycogen content was also observed, accompanied by reduced serum glucose levels. Histological and ultrastructural examination detected more lipid droplets accumulated in hepatocytes after PFOS exposure. Moreover, transcripitonal activity of lipid metabolism related genes suggests that PFOS toxicity is probably unrelevant to PPARα's transcription. The present study demonstrates a lipid disturbance caused by PFOS and thus point to its role in inhibiting the secretion and normal function of low density lipoproteins.

Prevention of endotoxin-induced monokine release by human low- and high-density lipoproteins and by apolipoprotein A-I.

Interaction of endotoxin (lipopolysaccharide [LPS]) with human lipoproteins is known to prevent the LPS-induced activation of human monocytes and release of cytokines (monokines). LPS was exposed to lipoprotein classes separated by ultracentrifugation and to apolipoprotein A-I. Then monocytes were added, and the LPS activation of monocytes was determined by measuring the induced monokines. Failure of LPS to induce monokine release was called LPS inactivation caused by lipoproteins or apolipoproteins. The LPS inactivation is shown to be a function of low-density lipoproteins. High-density lipoproteins inactivate LPS to a much lesser extent. The very-low-density lipoproteins cannot inactivate LPS. Lipid components seemed not absolutely required for LPS inactivation, because purified human apolipoprotein A-I without its physiological lipid complement also inhibits LPS-induced monokine release.