Adventitial nab-rapamycin injection reduces porcine femoral artery luminal stenosis induced by balloon angioplasty via inhibition of medial proliferation and adventitial inflammation.
BACKGROUND
Endovascular interventions on peripheral arteries are limited by high rates of restenosis. Our hypothesis was that adventitial injection of rapamycin nanoparticles would be safe and reduce luminal stenosis in a porcine femoral artery balloon angioplasty model.


RESULTS
Eighteen juvenile male crossbred swine were included. Single-injury (40%-60% femoral artery balloon overstretch injury; n=2) and double-injury models (endothelial denudation injury 2 weeks before a 20%-30% overstretch injury; n=2) were compared. The double-injury model produced significantly more luminal stenosis at 28 days, P=0.002, and no difference in medial fibrosis or inflammation. Four pigs were randomized to the double-injury model and adventitial injection of saline (n=2) or 500 μg of nanoparticle albumin-bound rapamycin (nab-rapamycin; n=2) with an endovascular microinfusion catheter. There was 100% procedural success and no difference in endothelial regeneration. At 28 days, nab-rapamycin led to significant reductions in luminal stenosis, 17% (interquartile range, 12%-35%) versus 10% (interquartile range, 8.3%-14%), P=0.001, medial cell proliferation, P<0.001, and fibrosis, P<0.001. There were significantly fewer adventitial leukocytes at 3 days, P<0.001, but no difference at 28 days. Pharmacokinetic analysis (single-injury model) found rapamycin concentrations 1500× higher in perivascular tissues than in blood at 1 hour. Perivascular rapamycin persisted ≥8 days and was not detectable at 28 days.


CONCLUSIONS
Adventitial nab-rapamycin injection was safe and significantly reduced luminal stenosis in a porcine femoral artery balloon angioplasty model. Observed reductions in early adventitial leukocyte infiltration and late medial cell proliferation and fibrosis suggest an immunosuppressive and antiproliferative mechanism. An intraluminal microinfusion catheter for adventitial injection represents an alternative to stent- or balloon-based local drug delivery.
From the Departments of Vascular Surgery (W.J.G., J.W., M.S.C., C.D.O.) and Pathology (C.A.J.), University of California, San Francisco; and Mercator MedSystems, Inc, San Leandro, California (K.S.).
Warren J
WJ
Gasper
Cynthia A
CA
Jimenez
Joy
J
Walker
Michael S
MS
Conte
Kirk
K
Seward
Christopher D
CD
Owens
D063194:Adventitia; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001167:Arteritis / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003251:Constriction, Pathologic / Q000209:etiology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology*; D005355:Fibrosis; D007269:Injections, Intra-Arterial; D007962:Leukocytes / Q000473:pathology; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
D020123:Sirolimus
coronary restenosis; drug delivery systems; peripheral arterial disease; sirolimus