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 placement of a carotid-jugular synthetic hemodialysis graft in a porcine model in vitro. Drug concentrations remained above the inhibitory concentrations for at least six weeks postoperatively. 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.

Paclitaxel coating of the luminal surface of hemodialysis grafts with effective suppression of neointimal hyperplasia

“…The proliferation and migration of vascular smooth muscle cells and myofibroblasts into the neointimal layer can result in a pathologic narrowing of the access. 2 There have been many efforts to prevent stenosis through inhibiting smooth muscle cell proliferation and migration using local delivery of potent antiproliferative agents such as paclitaxel or sirolimus. [3][4][5][6][7][8][9] We previously reported that paclitaxel coating of ePTFE grafts was effective in suppressing such neointimal hyperplasia and stenosis.…”

Autologous fat transplants to deliver glitazone and adiponectin for vasculoprotection

“…The minced fat was placed perivascular to the vein and the wound was sutured closed and the animals were allowed to recover. For efficacy studies, a porcine model of arteriovenous graft that has been described in detail previously [14, 15, 35, 36] was used. In sedated animals, under sterile conditions, a spiral-reinforced expanded synthetic polytetrafluoroethylene (PTFE) graft (7-cm length, 6-mm internal diameter) was placed between the common carotid artery and the ipsilateral external jugular vein such that blood flow from the carotid was partially shunted into the vein via the interposing graft.…”

“…We have previously reported the successful use of perivascular administration of sirolimus, an anti -proliferative immunosuppressant, using a biodegradable synthetic polymer to inhibit arteriovenous graft stenosis [14, 15]. However, swelling and exudate occurred at the site of polymer-drug administration in almost 17% of animals, suggesting the polymer-drug mixture may have triggered inflammation.…”

Novel Therapies for Hemodialysis Vascular Access Dysfunction

“…A single application of a polymer gel incorporated with the antiproliferative agent, paclitaxel, did inhibit neointimal hyperplasia in AVG in a dog model (17). Repeat application of a sirolimus-laden polymer gel through ultrasoundguided injection to the vein-graft anastomosis significantly inhibited neointimal hyperplasia at 6 weeks in the swine AVG model (63,69). Perivascular application of expression vectors to alter in vivo vascular gene expression to promote better access outcomes has been reported.…”