Abstract
Restenosis at a vascular anastomosis site is a major cause of graft failure and is difficult to prevent by conventional treatment. Perivascular drug delivery has advantages as drugs can be diffused to tunica media and subintima while minimizing the direct effect on endothelium. This in vivo study investigated the comparative effectiveness of paclitaxel, sirolimus, and sunitinib using a perivascular biodegradable microneedle cuff. A total of 31 New Zealand white rabbits were used. Rhodamine was used to visualize drug distribution (n = 3). Sirolimus- (n = 7), sunitinib- (n = 7), and paclitaxel-loaded (n = 7) microneedle cuffs were placed at balloon-injured abdominal aortae and compared to drug-free cuffs (n = 7). Basic histological structures were not affected by microneedle devices, and vascular wall thickness of the device-only group was similar to that of normal artery. Quantitative analysis revealed significantly decreased neointima formation in all drug-treated groups (p < 0.001). However, the tunica media layer of the paclitaxel-treated group was significantly thinner than that of other groups and also showed the highest apoptotic ratio (p < 0.001). Proliferating cell nuclear antigen (PCNA)-positive cells were significantly reduced in all drug-treated groups. Sirolimus or sunitinib appeared to be more appropriate for microneedle devices capable of slow drug release because vascular wall thickness was minimally affected.
Highlights
Application of biodegradable polymers for medical purposes—such as drug delivery, nanoparticle imaging technology, and soft tissue reconstruction—has been widely reported [1,2,3,4]
Continuous progress has been made, successful implementation of non-surgical treatments such as balloon angioplasty and endovascular stenting remains challenging due to restenosis derived from neointimal hyperplasia [12,13]
Extraluminal drug delivery using a perivascular biodegradable material was reported to reduce the recurrent rate [12,21]. Such an approach is advantageous as drugs can be diffused to the tunica adventitia and tunica media and subintima while minimizing the direct effect on endothelium [12]. To explore this advantage further, we developed a perivascular cuff containing an array of microneedles (MN) that has been shown to drastically increase drug delivery efficiency compared with devices without MN [20,22]
Summary
Application of biodegradable polymers for medical purposes—such as drug delivery, nanoparticle imaging technology, and soft tissue reconstruction—has been widely reported [1,2,3,4]. Extraluminal drug delivery using a perivascular biodegradable material was reported to reduce the recurrent rate [12,21] Such an approach is advantageous as drugs can be diffused to the tunica adventitia and tunica media and subintima while minimizing the direct effect on endothelium [12]. We aim to compare the effects other anti-proliferating drugs with paclitaxel on inhibition of neointima formation as well as thinning of tunica media when delivered through a MN cuff. Sirolimus is widely used in DES and has been shown to inhibit neointimal hyperplasia effectively through cytostatic mechanisms while sunitinib malate salt (sunitinib) was recently reported to show an inhibitory effect on neointimal hyperplasia These two drugs were compared with paclitaxel
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