title: Correlation of tissue drug concentrations with in vivo magnetic resonance images of polymer drug depot around arteriovenous graft.
abstract: Sustained delivery of anti-proliferative drugs to the perivascular area using an injectable polymeric platform is a strategy to inhibit vascular hyperplasia and stenosis. In this study, the concentrations of sirolimus in vascular tissues were evaluated after delivery using an injectable platform made of poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA). In order to optimize the drug release profile, the effect of two solvents or solid loading of the sirolimus into the polymer gel was first examined in vitro. The early release was slower with loading of dry drug into the polymer, compared to drug dissolution in solvents. Dry sirolimus was therefore used to load the polymer and applied to the perivascular surface of the graft-venous anastomosis at the time of surgical placement of a carotid-jugular synthetic hemodialysis graft in a porcine model. This was replenished by ultrasound-guided injection of additional drug-laden polymer at one, two and three weeks post-operatively. Magnetic resonance imaging (MRI) using pulse sequences specifically designed for optimal detection of the polymeric gel showed that the polymer injected post-operatively remained at the juxta-anastomotic perivascular site at two weeks. Sirolimus was extracted from various segments of the juxta-anastomotic tissues and the drug concentrations were determined using HPLC MS/MS. Tissue sirolimus concentrations at one and two weeks were highest near the venous anastomosis, which were approximately 100- to 500-fold greater than the concentrations necessary to inhibit vascular smooth muscle cell proliferation in vitro. Drug concentrations remained above the inhibitory concentrations for at least six weeks post-operatively. Thus, serial injections of sustained-delivery polymer gel loaded with sirolimus can provide high localized concentrations at target vascular tissues and thus may be useful for the prevention and treatment of vascular proliferative disorders such as hemodialysis graft stenosis. In addition, MRI is useful for the monitoring of the location of the drug depot.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, 301 Skaggs Hall, 30 South 2000 East, Salt Lake City, UT 84112, USA.
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Owen
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.forename: William G
authors.initials: WG
authors.lastname: Sanders
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
authors.forename: Christi M
authors.initials: CM
authors.lastname: Terry
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D004339:Drug Compounding; D005782:Gels; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control*; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016014:Linear Models; D018810:Magnetic Resonance Angiography; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D011098:Polyglactin 910 / Q000008:administration & dosage / Q000737:chemistry*; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012995:Solubility; D034421:Sus scrofa; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005782:Gels; C528571:poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid); D011098:Polyglactin 910; D011092:Polyethylene Glycols; D020123:Sirolimus
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