A polyoxyethylene sorbitan oleate modified hollow gold nanoparticle system to escape macrophage phagocytosis designed for triple combination lung cancer therapy via LDL-R mediated endocytosis.

Presently, a combination of chemotherapy, radiotherapy, thermotherapy, and other treatments has become a hot topic of research for the treatment of cancer, especially lung cancer. In this study, novel hollow gold nanoparticles (HGNPs) were used as drug carriers, and in order to improve the targeting ability of HGNPs to a lung tumor site, polyoxyethylene sorbitol oleate (PSO) was chosen here as a target ligand since it can be specifically recognized by the low-density lipoprotein (LDL) receptor which is usually over expressed on A549 lung cancer cells. In this way, a PSO-modified doxorubicin-loaded HGNP drug delivery system (PSO-HGNPs-DOX) was constructed and its physicochemical properties, photothermal conversion ability, and drug release of PSO-HGNPs-DOX was investigated. Further, the effects of triple combination therapy, the intracellular uptake, and the ability to escape macrophage phagocytosis of PSO-HGNPs-DOX were also studied using A549 cells in vitro. In addition, an in vivo mouse model was also used to study the targeting of PSO-HGNPs-DOX to lung cancer. PSO-HGNPs-DOX demonstrated a good triple therapeutic effect for lung cancer (A549 cell viability was only 10% at 500 µM) by LDL receptor mediated endocytosis and was able to escape macrophage phagocytosis to enhance its accumulation at the target site. Therefore, PSO-HGNPs-DOX is a novel, safe, promising, and targeted drug carrier designed for triple combination lung cancer therapy which should be further studied for such applications.

Low-density lipoprotein receptor-related protein-1 facilitates heme scavenging after intracerebral hemorrhage in mice.

Heme-degradation after erythrocyte lysis plays an important role in the pathophysiology of intracerebral hemorrhage. Low-density lipoprotein receptor-related protein-1 is a receptor expressed predominately at the neurovascular interface, which facilitates the clearance of the hemopexin and heme complex. In the present study, we investigated the role of low-density lipoprotein receptor-related protein-1 in heme removal and neuroprotection in a mouse model of intracerebral hemorrhage. Endogenous low-density lipoprotein receptor-related protein-1 and hemopexin were increased in ipsilateral brain after intracerebral hemorrhage, accompanied by increased hemoglobin levels, brain water content, blood-brain barrier permeability and neurological deficits. Exogenous human recombinant low-density lipoprotein receptor-related protein-1 protein reduced hematoma volume, brain water content surrounding hematoma, blood-brain barrier permeability and improved neurological function three days after intracerebral hemorrhage. The expression of malondialdehyde, fluoro-Jade C positive cells and cleaved caspase 3 was increased three days after intracerebral hemorrhage in the ipsilateral brain tissues and decreased with recombinant low-density lipoprotein receptor-related protein-1. Intracerebral hemorrhage decreased and recombinant low-density lipoprotein receptor-related protein-1 increased the levels of superoxide dismutase 1. Low-density lipoprotein receptor-related protein-1 siRNA reduced the effect of human recombinant low-density lipoprotein receptor-related protein-1 on all outcomes measured. Collectively, our findings suggest that low-density lipoprotein receptor-related protein-1 contributed to heme clearance and blood-brain barrier protection after intracerebral hemorrhage. The use of low-density lipoprotein receptor-related protein-1 as supplement provides a novel approach to ameliorating intracerebral hemorrhage brain injury via its pleiotropic neuroprotective effects.

Efecto de la LDL modificada en la expresión de adipofilina en macrófagos y células musculares lisas de la pared vascular. Implicaciones para el desarrollo de arteriosclerosis / Effect of modified LDL in the expression of adipocyte differentiation-related protein in macrophages and vascular smooth muscle cells. Implications for atherosclerosis progression

Objetivo: Analizar si la unión e interiorización de la LDL modificada por agregación (LDLag) puede inducir la expresión de la proteina adipofilina (ADRP), un marcador de acumulación lipídica, en las células musculares lisas de la pared vascular (CMLV) y macrófagos humanos. Resultados: La LDLag induce la sobreexpresión de ADRP tanto a nivel de ARNm (PCR tiempo real) como a nivel de proteina («western blot») en CMLV (ARNm: 3.06-veces; proteina: 8.58-veces) y también en macrófagos (ARNm: 3.5-veces; proteina: 3.71-veces). Los estudios immunohistoquímicos evidenciaron una alta colocalización entre ADRP y CMLV y también entre ADRP y macrófagos en placas ateroscleróticas avanzadas ricas en lípido. Conclusiones: La captación de LDLag mediante el receptor lipoproteíco LRP1 juega un papel primordial en la formación de células espumosas a partir de macrófagos y de CMLV y, por tanto, en la progresión de la lesión aterosclerótica (AU)

Aims: The objectives of this work were to analyze whether aggregated LDL (agLDL) uptake modulates ADRP expression levels in human vascular smooth muscle cells (VSMC) and macrophages (HMDM). Methods and Results: AgLDL strongly upregulated ADRP mRNA (Real-time PCR) and protein expression (western blot) in human VSMC (mRNA: by 3.06-fold; protein: 8.58-fold) and HMDM (mRNA: by 3.5-fold; protein: by 3.71-fold).. Immunohystochemical studies evidence a high colocolocalization between ADRP/macrophages and ADRP/VSMC in advanced lipid-enriched atherosclerotic plaques. Conclusions:These results demonstrate that agLDL-LRP1 engagement induces ADRP overexpression in both HMDM and human VSMC. ADRP is highly expressed in advanced lipid-enriched human atherosclerotic plaques. Therefore, LRP1-mediated agLDL uptake might play a pivotal role on vascular foam cell formation and atherosclerotic plaque progression (AU)