| Along with the invasive techniques, such as percutaneous transluminal coronary angioplasty (PTCA) and percutaneous coronary intervention (PCI), were currently performed as effective procedures to reduce the severity of stenotic coronary atherosclerotic disease,restenosis became a principal complication and significantly limited the long-term prognosis. It is attributed to Atery remodeling and proliferation of smooth muscle cells in the intima,which subsequent from vascular smooth muscle cell (VSMC) activation and migration caused by PTCA.The mechanisms of vessel wall remodeling include elastic recoil, enhanced extracellular matrix synthesis and thrombus formation. polymer coating Durg-eluting stent (DES) was widely used to prevent restenosis. Though the DES can reduce restenosis significantly, it also induced malendothelialization,coronary aneurysm and life threaten in-stent thromboformation.Vascular Endothelial Cell Growth Factor (VEGF) is a kind of glycopeptide secreted by a variety of vascularized tissues. The reported activities of VEGF include stimulation of endothelial cell growth, angiogenesis, and capillary permeability. Human VEGF is a45kDa homodimeric protein consisting of two165amino acid polypeptide chains. Subsequent characterizations of the VEGF isoforms have revealed five subtypes VEGF121, VEGF145,VEGF165, VEGF189, and VEGF206. Two subtypes of VEGF receptors, Flt-1(VEGFR-1) and FLK-1/KDR (VEGFR-2) have been identified on endothelial cells and are thought to mediate the mitogenic effects of VEGF, with the VEGFR-2receptor thought to be the dominant mediator of endothelial division. Thus far these receptors have only been localized to macrophages and endothelial cells, which explains the specificity of the VEGF response to endothelial cells as opposed to other vascular cell types. The prevention of restenosis post PCI procedure by systemic pharmacologic therapy is inadequate because of the toxic and side-effect related to overdosage drug administration. Meanwhile It caused poor efficacy of drug disposition and metabolism. Locally drug delivered therapeutics can provide a operative way which can keep the drug concentration in the target site of the artery while decreasing the total drug burden greatly. A nanoparticle delivery system is well suited for the treatment of restenosis since local or targeted delivery can be achieved, lowering systemic toxicity, while reaching specific cell types in sufficient concentrations for the necessary period of time.The GENIE CatheterTM is a new local drug delivery catheter designed to deliver various liquid therapeutic agents, such as paclitaxel, into the arteries. Using the GENIE CatheterTM Liquid drug can reach most of the vessel wall without the vascular trauma of plaque crushing. A concept of GENIE CatheterTM Therapy has been developed by exposing coronary arteries to low dose (10μM) of paclitaxel to prevent stenosis. This approach has been described as a potential alternative/complement to Drug Eluting Stent (DES) in specific indications.Paclitaxel (Taxol) is a microtubule-stabilizing compound with potent antitumor activity. It influences the cytoskeleton equilibrium by increasing the assembly of altered microtubules, thereby inducing cellular modifications that result in reduced proliferation, migration and signal transduction.This study sought to engineer and characterize a biodegradable nanoparticles containing Paclitaxel and VEGF which use co-polymer polylactic-polyglycolic acid(PLGA) as the carrier matrix. Then, the present study was designed to observe the effects of Paclitaxel/VEGF-loaed PLGA nanoparticles on vascular endothelial cell and vascular smooth muscle cell.Biodegradable Paclitaxel/VEGF-loaed PLGA nanoparticles was successfully constructed by emulsification solvent-evaporation technique. And the average diameter of nanoparticles was78.82nm measured by submicrolaser defractometer, average Drug-loading rate was28.58%,75%loading dose released in2weeks.A predetermined concentration Paclitaxel/VEGF-loaed PLGA nanoparticles suspensions of a was then infused into the arteries for various durations. The drug levels of target arterial segments were analyzed by High Performance Liquid Chromatography (HPLC). From the drug loading the Nanoparticles and the drug levels in the artery, the quantity of nanoparticles retained was calculated and expressed as microgram per10mg dry arteries. A single5mins infusions of nanoparticles suspension (2atm) were achieved local tissue concentrations of22.45±2.64μg/10mg and4.64±0.77μg/10mg dry-weight at7day and14day after drug delivery, respectively. The concentration of local tissure was under the minimal limit that was measured with HPLC method.In the second part of study, physiological saline,Paclitaxel-loaed PLGA nanoparticles,VEGF-loaed PLGA nanoparticles and Paclitaxel/VEGF-loaed PLGA nanoparticles were perfused into balloon-injured abdominal arteries of New Zealand rabbits model by a local drug delivery GENIE catheter at2-3atm over a5-min period respectively. Histologically, proliferative index and NEELA EELA ratio were reduced significantly in Paclitaxel/VEGF-loaed PLGA nanoparticles-treated animals compared with controls(all P<0.05). Compared with control groups, there were no significant difference of the MMP-2and TIMP-2protein levels calculated by the results of immunocytochemical strain.We demonstrate that Paclitaxel/VEGF-loaed PLGA nanoparticles can prevents balloon-injured abdominal arteries of New Zealand rabbits model through local drug delivery GENIE system.
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