Periadventitial Rapamycin-Eluting Microbeads Promote Vein Graft Disease in Long-Term Pig Vein-Into-Artery Interposition Grafts

Rajathurai, Thirumaran; Rizvi, S. Imran; Lin, Hua; Angelini, Gianni D; Newby, Andrew C.; Murphy, Gavin J.

doi:10.1161/circinterventions.109.864660

Cited by 34 publications

(26 citation statements)

References 25 publications

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“…Thus, there is an increase in local drug concentration without significant systemic effects [117]. There have been several preclinical studies designed to extend the dwell time around the vessel, including encapsulation of the drug in microspheres, or holding the treatment in place using gels made of fibrin or pluronic material [116,[118][119][120][121]]. An alternative solution may be to expose the vessel to the cell that makes the treatment, rather than present the drug directly to the vessel [122,123].…”

Section: Perivascular Deliverymentioning

confidence: 99%

“…Periadventitial administration of rapamycineluting microbeads to extend the rapamycin therapy was investigated, but, once again, while the drug was effective at early time-points, there was catch-up by 12 weeks after engraftment. Increasing the dose of rapamycin led to local toxicity, with graft rupture, inhibition of neoangiogenesis and accelerated neointimal formation [121].…”

Section: Cytostatic and Immunosuppressivementioning

confidence: 99%

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Targeted Treatments for Restenosis and Vein Graft Disease

Thomas

2012

ISRN Vascular Medicine

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Surgery to restore blood flow in arteries blocked by atherosclerotic plaque is a common treatment in cardiovascular disease. Longterm complications of surgical treatment are vein graft disease and restenosis, a renarrowing of the blood vessel after bypass or removal of the culprit atherosclerotic plaque. Attempts to prevent or treat these complications by systemic pharmacological approaches have been largely unsuccessful in the clinic. This has led to an interest in developing targeted or locally delivered strategies. This paper discusses many of the various site-delivered therapies that are under examination as potential antirestenotic and antivein graft disease agents (including antithrombotic, antiproliferative, and anti-inflammatory agents) and why many therapies developed in animal models fail in clinical trials. Techniques of targeted delivery (including stents, "magic bullets," and adventitial delivery) and delivery systems (including nanoparticles and the use of gene therapy) are also discussed.

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Section: Perivascular Deliverymentioning

confidence: 99%

Section: Cytostatic and Immunosuppressivementioning

confidence: 99%

Targeted Treatments for Restenosis and Vein Graft Disease

Thomas

2012

ISRN Vascular Medicine

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“…A number of methods have been explored for perivascular delivery of anti-proliferative drugs to reconstructed arteries or veins using a variety of polymers as a vehicle, including drug-releasing polymer gel [8]/depots [9], microspheres [10, 11], cuffs [12], wraps/films [13–16], or meshes [17]. While each method has its own advantages, none has advanced to clinical trials, likely due to various limitations revealed in animal studies, such as moderate efficacy, lack of biodegradation, or mechanical stress to the blood vessel.…”

Section: Introductionmentioning

confidence: 99%

A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia

Takayama

Goel

Shi

et al. 2014

Journal of Controlled Release

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Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50 days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90 days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel’s anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery.

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“…[6][7][8] However, some reports have indicated that inhibition of neointimal formation leads to incomplete neointimal coverage associated with a high rate of thrombus formation after stenting. [9][10][11] Subacute thrombosis might be caused by delayed recovery of the intima and a hypersensitivity response to the drug stent. [11][12][13] Therefore, continued efforts to improve polymer biocompatibility are warranted.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] Subacute thrombosis might be caused by delayed recovery of the intima and a hypersensitivity response to the drug stent. [11][12][13] Therefore, continued efforts to improve polymer biocompatibility are warranted.…”

Section: Introductionmentioning

confidence: 99%

Pretreatment with intraluminal rapamycin nanoparticle perfusion inhibits neointimal hyperplasia in a rabbit vein graft model

Cao²,

Zhang³

et al. 2010

IJN

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Purpose: Poly lactic-co-glycolic acid nanoparticles (PLGA-NP) are widely used as a biodegradable biomaterial in medicine. Rapamycin-eluting stents have been used for prevention of restenosis during surgery. This study investigated the effect of pretreatment with intraluminal perfusion of carbopol-encapsulated rapamycin-loaded PLGA nanoparticles (RAP-PLGA-NP) on neointimal hyperplasia in a rabbit vein graft model. Methods: A segment of common carotid artery was replaced with a segment of external jugular vein in 60 rabbits which were then separated into four treatment groups, ie, Group 1, in which vein grafts were pretreated with intraluminal RAP-PLGA-NP perfusion, Group 2 in which vein grafts underwent equivalent empty vehicle (PLGA-NP) perfusion, Group 3, in which vein grafts received no treatment, and Group 4, which served as a sham operation group receiving normal vein contrast. On postoperative day 28, the grafts and normal veins were harvested for histologic examination, flow cytometry analysis, and high-performance liquid chromatography measurement. Results: Compared with Group 1, the intima of the grafts were thickened, the ratio of intimal area to vessel area increased, and the collagen volume index of the vein grafts increased significantly in Groups 2 and 3. The cell proliferation index in Group 1 (21.11 ± 3.15%) was much lower than that in Group 2 (30.35 ± 2.69%) and in Group 3 (33.86 ± 8.72%). By highperformance liquid chromatography measurement, retention of rapamycin was detected in Group 1 (11.2 ± 0.37 µg/10 mg) 28 days after single drug perfusion. Conclusion: Pretreatment with intraluminal RAP-PLGA-NP perfusion may inhibit neointimal hyperplasia in vein grafts by penetrating into local tissue and limiting cell proliferation.

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Periadventitial Rapamycin-Eluting Microbeads Promote Vein Graft Disease in Long-Term Pig Vein-Into-Artery Interposition Grafts

Abstract: Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease.

Cited by 34 publications

References 25 publications

Targeted Treatments for Restenosis and Vein Graft Disease

Targeted Treatments for Restenosis and Vein Graft Disease

A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia

Pretreatment with intraluminal rapamycin nanoparticle perfusion inhibits neointimal hyperplasia in a rabbit vein graft model

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