Combination of Paclitaxel and Nitric Oxide as a Novel Treatment for the Reduction of Restenosis

The combination of a nitric oxide (NO) donor and a paclitaxel−NO donor conjugate coated on a vascular stent was tested in a rabbit iliac artery model of stenosis as a potential therapy for restenosis. Paclitaxel was conjugated with a NO donor at the 7-position to give compound <BO>7</BO>. An adamantane-based NO donor <BO>14</BO> was synthesized and combined with <BO>7</BO> to provide a burst of NO in the first few critical hours following injury to the vessel wall. Both <BO>7</BO> and <BO>14</BO> demonstrated antiproliferative activity (IC<INF>50</INF> = 20 nM and 15 μM, respectively) and antiplatelet activity (IC<INF>50</INF> = 10 and 1 μM, respectively). Stents were coated with a layer of a polymer containing test compounds. The total amount of NO eluted from the stents after a 6 h implantation in the rabbit iliac artery was 35%, 95%, and 69% of the original content for the stents coated with <BO>7</BO>, <BO>14</BO>, and the combination of <BO>7</BO> and <BO>14</BO>, respectively. The antistenotic activity of <BO>7</BO> and <BO>14</BO> was determined in a 28-day rabbit model with two control groups (uncoated stents and polymer-coated stents) and two study groups (paclitaxel-coated stents and stents coated with the combination of <BO>7</BO> and <BO>14</BO>). Polymer-coated stents caused inflammation and increased stenosis by 39% when compared to the uncoated stents. The stents coated with <BO>7</BO> plus <BO>14</BO> were as good as the uncoated stents, 41% better than the polymer-coated stents and 34% better than the paclitaxel-coated stents. These data indicate a beneficial effect of adding NO to an antiproliferative agent (paclitaxel) and suggest a potential therapeutic combination for the treatment of stenotic vessel disease.