sirolimus and betadex

Topics: Acetylation; Animals; Atherosclerosis; beta-Cyclodextrins; Delayed-Action Preparations; Drug Delivery Systems; Hydrogen-Ion Concentration; Immunosuppressive Agents; Inflammation; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Plaque, Atherosclerotic; RAW 264.7 Cells; Reactive Oxygen Species; Sirolimus

Coronary arterial disease (CAD) remains the leading cause of death globally. Percutaneous coronary interventions are frequently used nonsurgical techniques for treating CAD, which may unfortunately lead to arterial restenosis. Currently, there are no effective drugs that can thoroughly prevent restenosis. We hypothesize inflammation-triggerable nanomedicines may function as effective therapeutics for targeted therapy of restenosis, by preferentially releasing their payload at the diseased site. To demonstrate our hypothesis and develop targeted nanotherapies for restenosis, this study was designed to examine effectiveness of nanomedicines responsive to the inflammatory microenvironment with mild acidity and high reactive oxygen species (ROS). To this end, an acetalated β-cyclodextrin (β-CD) material (Ac-bCD) was synthesized as a pH-responsive carrier material, while a ROS-responsive material (Ox-bCD) was produced by hydrophobic functionalization of β-CD with an oxidation-labile group. Based on these two responsive materials, either pH- or ROS-responsive nanoparticles (NPs) were produced by a nanoprecipitation technique and fully characterized. Using rapamycin (RAP) as a candidate drug, responsive nanotherapies were fabricated. In vitro hydrolysis and release studies confirmed these nanovehicles and nanotherapies exhibited desirable responsive behaviors. Both in vitro cell culture and in vivo evaluations revealed their good safety profile. These responsive NPs could be effectively internalized by rat vascular smooth muscle cells, which in turn notably potentiated anti-proliferation and anti-migration activities of RAP. After intravenous (i.v.) injection, NPs may be accumulated at the injured site in the carotid artery of rats subjected to balloon angioplasty injury. Compared with a non-responsive nanotherapy based on poly(lactide-co-glycolide), treatment with either pH- or ROS-responsive nanotherapy by i.v. injection more effectively attenuated neointimal hyperplasia in a rat model of arterial restenosis. Accordingly, nanotherapeutics responsive to the inflammatory microenvironment hold great potential for the management of vascular restenosis by selectively releasing drug molecules at the inflamed sites.

Topics: Animals; Arteritis; beta-Cyclodextrins; Cells, Cultured; Cellular Microenvironment; Coronary Restenosis; Immunosuppressive Agents; Male; Molecular Targeted Therapy; Nanocapsules; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sirolimus; Treatment Outcome

Niemann-Pick Type C disease (NPC) is a lethal, autosomal recessive disorder caused by mutations in the NPC1 and NPC2 cholesterol transport proteins. NPC's hallmark symptoms include an accumulation of unesterified cholesterol and other lipids in the late endosomal and lysosomal cellular compartments, causing progressive neurodegeneration and death. Although the age of onset may vary in those affected, NPC most often manifests in juveniles, and is usually fatal before adolescence. In this study, we investigated the effects of various drugs, many of which modify the epigenetic control of NPC1/NPC2 gene expression, in lowering the otherwise harmful elevated intracellular cholesterol levels in NPC cells. Our studies utilized a previously described image analysis technique, which allowed us to make quantitative comparisons of the efficacy of these drugs in lowering cholesterol levels in a common NPC1 mutant model. Of the drugs analyzed, several that have been previously studied (vorinostat, panobinostat, and β-cyclodextrin) significantly lowered the relative amount of unesterified cellular cholesterol, consistent with earlier observations. In addition, a novel potential treatment, rapamycin, likewise alleviated the NPC phenotype. We also studied combinations of effective compounds with β-cyclodextrin; the addition of β-cyclodextrin significantly enhanced the cholesterol-lowering activity of vorinostat and panobinostat, but had mixed effects with rapamycin. Collectively, these results may provide a basis for the eventual development of improved NPC therapies.

Topics: Azacitidine; beta-Cyclodextrins; Cells, Cultured; Child; Child, Preschool; Chloroquine; Chlorpromazine; Cholesterol; Decitabine; Dose-Response Relationship, Drug; Drug Synergism; Female; Fibroblasts; Humans; Hydroxamic Acids; Indoles; Intracellular Space; Male; Microscopy, Fluorescence; Mutation; Niemann-Pick Disease, Type C; Panobinostat; Sirolimus; Vorinostat