Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles

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Abstract

Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis.

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Most cited references 26

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Protected carotid-artery stenting versus endarterectomy in high-risk patients.

Jay S Yadav, Mark Wholey, Richard Kuntz … (2004)

Carotid endarterectomy is more effective than medical management in the prevention of stroke in patients with severe symptomatic or asymptomatic atherosclerotic carotid-artery stenosis. Stenting with the use of an emboli-protection device is a less invasive revascularization strategy than endarterectomy in carotid-artery disease. We conducted a randomized trial comparing carotid-artery stenting with the use of an emboli-protection device to endarterectomy in 334 patients with coexisting conditions that potentially increased the risk posed by endarterectomy and who had either a symptomatic carotid-artery stenosis of at least 50 percent of the luminal diameter or an asymptomatic stenosis of at least 80 percent. The primary end point of the study was the cumulative incidence of a major cardiovascular event at 1 year--a composite of death, stroke, or myocardial infarction within 30 days after the intervention or death or ipsilateral stroke between 31 days and 1 year. The study was designed to test the hypothesis that the less invasive strategy, stenting, was not inferior to endarterectomy. The primary end point occurred in 20 patients randomly assigned to undergo carotid-artery stenting with an emboli-protection device (cumulative incidence, 12.2 percent) and in 32 patients randomly assigned to undergo endarterectomy (cumulative incidence, 20.1 percent; absolute difference, -7.9 percentage points; 95 percent confidence interval, -16.4 to 0.7 percentage points; P=0.004 for noninferiority, and P=0.053 for superiority). At one year, carotid revascularization was repeated in fewer patients who had received stents than in those who had undergone endarterectomy (cumulative incidence, 0.6 percent vs. 4.3 percent; P=0.04). Among patients with severe carotid-artery stenosis and coexisting conditions, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy. Copyright 2004 Massachusetts Medical Society.

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Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg.

T Albrecht, Uwe Schwarzwälder, Jonathan C. Claussen … (2008)

Drug-eluting stents reduce restenosis in coronary arteries, but clinical trials have failed to prove their efficacy in peripheral arteries. We investigated the use of paclitaxel-coated angioplasty balloons and paclitaxel dissolved in the angiographic contrast medium during angioplasty of the leg. In a small, multicenter trial, we randomly assigned 154 patients with stenosis or occlusion of a femoropopliteal artery to treatment with standard balloon catheters coated with paclitaxel, uncoated balloons with paclitaxel dissolved in the contrast medium, or uncoated balloons without paclitaxel (control). The primary end point was late lumen loss at 6 months. The mean (+/-SD) age of the patients was 68+/-8 years, 24% were smokers, and 49% had diabetes. Twenty-seven percent of the lesions were total occlusions, and 36% were restenotic lesions. The mean lesion length was 7.4+/-6.5 cm. There were no significant differences in baseline characteristics between the groups. There were no adverse events attributable to the paclitaxel-coated balloons. At 6 months, the mean late lumen loss was 1.7+/-1.8 mm in the control group, as compared with 0.4+/-1.2 mm (P<0.001) in the group treated with paclitaxel-coated balloons and 2.2+/-1.6 mm (P=0.11) in the group treated with paclitaxel in the contrast medium. The rate of revascularization of target lesions at 6 months was 20 of 54 (37%) in the control group, 2 of 48 (4%) in the group treated with paclitaxel-coated balloons (P<0.001 vs. control), and 15 of 52 (29%) in the group treated with paclitaxel in the contrast medium (P=0.41 vs. control); at 24 months, the rates increased to 28 of 54 (52%), 7 of 48 (15%), and 21 of 52 (40%), respectively. Use of paclitaxel-coated angioplasty balloons during percutaneous treatment of femoropopliteal disease is associated with significant reductions in late lumen loss and target-lesion revascularization. No significant benefit is seen with the use of a paclitaxel-containing contrast medium. (ClinicalTrials.gov number, NCT00156624 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.

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Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery.

Bernhard R Brehm, W Kunert, D I Axel … (1997)

The antineoplastic compound paclitaxel (Taxol) causes an increased assembly of extraordinarily stable microtubules. The present study was designed to characterize the effects of paclitaxel on proliferation and migration of human arterial smooth muscle cells (haSMCs) in vitro and on neointima formation in an in vivo experimental rabbit model. Both monocultures of haSMCs and cocultures with human arterial endothelial cells (haECs) were used. Cell growth after 4, 8, and 14 days was determined in the absence or presence of platelet-derived growth factor-AB (PDGF-AB), basic fibroblast growth factor (bFGF), or thrombin. Nonstop paclitaxel exposure, as well as single-dose applications of paclitaxel for 24 hours or even 20 minutes (0.1 to 10.0 micromol/L), caused a complete and prolonged inhibition of haSMC growth up to day 14, with an IC50 of 2.0 nmol/L. Mitogens or cocultures with stimulating haECs did not significantly attenuate paclitaxel-induced effects. Immunohistochemistry showed characteristic cytoskeletal changes predominantly in the microtubule network. Additionally, in 20 male New Zealand White rabbits, intimal plaques were produced by electrical stimulation. In 10 animals, paclitaxel was locally applied by use of microporous balloons. Histologically, the intima wall area, wall thickness, and degree of stenosis were reduced significantly in paclitaxel-treated animals compared with controls. Our data show that paclitaxel inhibits haSMC proliferation and migration in a dose-dependent manner in monocultures and cocultures even in the presence of mitogens. Furthermore, paclitaxel prevents neointima formation in rabbits after balloon angioplasty. The long-lasting effect after just several minutes' exposure time makes this lipophilic substance a promising candidate for local antiproliferative therapy of restenosis.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 22 February 2016

Publication date Collection: 2016

Volume: 6

Electronic Location Identifier: 21683

Affiliations

[1 ]Department of Cardiology, Children’s Hospital of Chongqing Medical University , Chongqing, China

[2 ]Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics , Chongqing, China

[3 ]Department of Pediatrics, Mianyang Central Hospital , Mianyang, Sichuan, China

[4 ]Department of Radiology, 324 Hospital of the PLA , Chongqing, China

[5 ]Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen, China

[6 ]Shenzhen Key Laboratory of Nanobiomechanics, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen, China

Author notes

[a ] jixiaojuan2003@ 123456163.com

[b ] fei.yan@ 123456siat.ac.cn

[*]

These authors contributed equally to this work.

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Publisher Item ID: srep21683

DOI: 10.1038/srep21683

PMC ID: 4761943

PubMed ID: 26899550

SO-VID: a49cc1f9-3579-4578-b85f-160b5989e68b

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Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles

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Most cited references 26

Protected carotid-artery stenting versus endarterectomy in high-risk patients.

Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg.

Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery.

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