Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel.
BACKGROUND
Neointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibility of local drug delivery to inhibit neointimal hyperplasia at dialysis grafts in a canine model.


METHODS
Bilateral polytetrafluoroethylene loop grafts (10-cm length and 6-mm internal diameter) were placed between the femoral artery and ipsilateral femoral vein of five mongrel dogs. At the time of surgery or 1 to 5 weeks later, 2 mL of a thermosensitive biodegradable copolymer (ReGel) mixed with 0.26 mg or 0.65 mg paclitaxel were applied to the external surface of one graft around the anastomoses to provide a depot for sustained release of the drug. ReGel alone without paclitaxel was applied to the contralateral graft as a control. The grafts and the connecting vessels were explanted at eight or nine weeks, and the cross-sections were examined histologically. The degree of hyperplasia at the anastomoses was graded by five blinded independent reviewers, with scores ranging from 0 to 5.


RESULTS
The median (25th-75th percentile) hyperplasia score of both arterial and venous anastomoses was 1.80 (0.90-3.05) in the grafts treated with ReGel alone, and 0.95 (0.70-1.50) in the grafts treated with ReGel/paclitaxel (N= 8; P < 0.05 by Wilcoxon signed rank test). There were no noticeable localized or systemic complications attributed to the treatments in these animals. Paclitaxel levels in the plasma obtained from forelimb veins were undetectable (<10 ng/mL).


CONCLUSIONS
These results suggest that the local delivery of antiproliferative agents using a thermosensitive, injectable biodegradable copolymer (ReGel) for sustained delivery is a promising strategy to inhibit neointimal hyperplasia of arteriovenous hemodialysis grafts.
Masaki
Takahisa
T
Departments of Medicine, Bioengineering, Pathology, Pharmaceutics, and Surgery, and Animal Resource Center, University of Utah, Salt Lake City, Utah, USA.
Rathi
Ramesh
R
Zentner
Gaylen
G
Leypoldt
John K
JK
Mohammad
Syed F
SF
Burns
Gregory L
GL
Li
Li
L
Zhuplatov
Sergey
S
Chirananthavat
Thanit
T
Kim
Seung-Jung
SJ
Kern
Steven
S
Holman
John
J
Kim
Sung Wan
SW
Cheung
Alfred K
AK
D000818:Animals; D001807:Blood Vessel Prosthesis; D004285:Dogs; D005260:Female; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011108:Polymers; D011138:Polytetrafluoroethylene; D006435:Renal Dialysis; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
D011108:Polymers; D011138:Polytetrafluoroethylene; D017239:Paclitaxel