Published online before print February 21, 2008, doi: 10.1161/ATVBAHA.107.156281
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© 2008 American Heart Association, Inc.
Integrated Physiology/Experimental Medicine |
Intramural Delivery of Rapamycin With 
vβ3-Targeted Paramagnetic Nanoparticles Inhibits Stenosis After Balloon Injury
From the Division of Cardiology (T.C., H.Z., J.S.A., T.A.W., G.H., S.A.W., G.M.L.), Washington University School of Medicine, Saint Louis, Mo; and Philips Medical Systems (S.D.C.), Andover, Mass.
Correspondence to Tillmann Cyrus, MB, MD, Washington University School of Medicine, 4320 Forest Park Avenue, Suite 101, Campus Box 8215, Saint Louis, MO 63108. E-mail tcyrus{at}im.wustl.edu
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Abstract |
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Background— Drug eluting stents prevent vascular restenosis but can delay endothelial healing. A rabbit femoral artery model of stenosis formation after vascular injury was used to study the effect of intramural delivery of
vβ3-integrin-targeted rapamycin nanoparticles on vascular stenosis and endothelial healing responses.
Methods and Results— Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were locally treated with either (1) vβ3-targeted rapamycin nanoparticles, (2) vβ3-targeted nanoparticles without rapamycin, (3) nontargeted rapamycin nanoparticles, or (4) saline. Intramural binding of integrin-targeted paramagnetic nanoparticles was confirmed with MR molecular imaging (1.5 T). MR angiograms were indistinguishable between targeted and control arteries at baseline, but 2 weeks later they showed qualitatively less luminal plaque in the targeted rapamycin treated segments compared with contralateral control vessels. In a first cohort of 19 animals (38 vessel segments), microscopic morphometric analysis of the rapamycin-treated segments revealed a 52% decrease in the neointima/media ratio (P<0.05) compared to control. No differences (P>0.05) were observed among balloon injured vessel segments treated with vβ3-targeted nanoparticles without rapamycin, nontargeted nanoparticles with rapamycin, or saline. In a second cohort of 29 animals, endothelial healing followed a parallel pattern over 4 weeks in the vessels treated with vβ3-targeted rapamycin nanoparticles and the 3 control groups.
Conclusions— Local intramural delivery of vβ3-targeted rapamycin nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury.
Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were treated locally with either: (1) vβ3-targeted rapamycin nanoparticles, (2) vβ3-targeted nanoparticles without rapamycin, (3) nontargeted rapamycin nanoparticles, or (4) saline. Intramural delivery of vβ3-targeted rapamycin nanoparticles inhibited stenosis at 2 weeks without delaying endothelial healing following balloon injury over 4 weeks.
Key Words: nanoparticles • MRI • restenosis • rapamycin • drug delivery
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Introduction |
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Vascular restenosis negates the clinical benefit of percutaneous angioplasty and can elicit recurrent anginal discomfort, myocardial damage, or impede peripheral circulation. Drug-eluting stents (DES) treat postangioplasty recoil and deliver antiproliferative agents, which ameliorate the restenosis response to coronary angioplasty.1–7 However, placement of these devices in small target vessels, very long lesions, difficult anatomic locations (eg, peripheral bifurcations, or in kinked vessels), or in chronic total vascular occlusions may not always be feasible. Conversely, in large diameter arteries, such as iliac or femoral arteries, placement of stents with large interstrut distances often requires higher drug loading, which may increase the potential for side-effects or risk inadequate drug delivery.8,9
See accompanying article on page 801
Recently, late in-stent thrombosis has been associated with DES, reflecting the challenge of reendothelialization when delivering antiproliferative agents into the vessel wall from the stent-intima interface.10,11 Aggressive dual (and occasion-ally triple) antiplatelet therapy is used for 6 months to a year to avoid acute thrombosis, but we now recognize that some patients are nonresponders to 1 or more of these drugs.12,13 Discontinuation of antiplatelet therapy secondary to noncompliance, bleeding complications, or the need for emergent surgery increases the likelihood for thrombotic complication, which is associated with a 45% fatality rate in this small, but significant population of patients.9 Moreover, the risk of late in-stent thrombosis may persist up to 30 months after DES implantation.14,15
We have reported that perfluorocarbon nanoparticles can be modified to target a variety of cellular and matrix biomarkers in vivo for imaging with MRI or ultrasound to delineate the morphology of the balloon-injured wall.16,17 In addition, drugs incorporated into the outer lipid membrane of these nanoparticles can be delivered through fusion with lipid transfer to the target cell membrane after binding through a process we have termed "contact facilitated drug delivery."18
The objective of this study was to determine (1) whether vβ3-targeted nanoparticles with rapamycin delivered locally could inhibit acute stenosis after balloon overstretch and (2) whether endothelial healing is impaired by intramural vβ3-targeted nanoparticles with rapamycin.
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Methods |
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Preparation of Integrin-Targeted Rapamycin Nanoparticles
Ligand-targeted and nontargeted paramagnetic perfluorocarbon nanoparticle emulsions were formulated as previously described.19,20 Nanoparticles comprised of 20% (v/v) perfluorooctylbromide (PFOB; Exfluor Research), 1.5% (wt/vol) of a surfactant comixture, 1.7% (wt/vol) glycerin, and water for the balance. The surfactant comixture included 69.9 mol% lecithin (Avanti Polar Lipids, Inc), and 0.1 mol% peptidomimetic vitronectin antagonist21–23 (Bristol-Myers Squibb, Medical Imaging) coupled to MPB-polyethylene glycol (PEG)2000-phosphatidylethanolamine (Northern Lipids, Inc), and 30 mol% gadolinium diethylene-triamine-pentaacetic acid-bis-oleate (Gateway Chemical Technologies). Rapamycin was incorporated into the surfactant layer at a concentration of 0.4 mol% and substituted for phosphatidylcholine in the lipid mixture. Control
vβ3-targeted paramagnetic nanoparticles excluded the rapamycin. The nominal sizes for each formulation were 293 nm and 281 nm for the rapamycin and drug-free nanoparticles, respectively (Malvern Zetasizer, Malvern Instruments).
Drug Analysis
Rapamycin was analyzed using a reversed-phase high-performance liquid chromatography (HPLC) system (Waters Corporation). Separation conditions included: a GRACE VYDAC C18, 5 µm, 4.6x250 mm column, a 50% acetonitrile in water mobile phase at 35°C, and a 1 mL/min flow rate. For the dissolution studies, 250-µL aliquots of rapamycin nanoparticle emulsion were added to each of 3 dialysis tubes and placed in autosampler vial filled with 3.5 mL releasing medium (0.9% NaCl, 0.2 mg/mL human serum albumin; 0.05% NaN3 in 500 mL, pH 6). Samples were placed on a rocker and incubated at 37°C for 1 to 3 days; releasing medium was replaced each day, and 3 samples analyzed for each day.
Animal Study Procedures
All studies were approved by the Washington University Animal Studies Committee and are based on National Institutes of Health laboratory standards. Two-month-old male New Zealand white (NZW) rabbits (2.4 to 2.9 kg) were fed a 1% cholesterol diet for 4 months. While causing atherosclerotic plaque formation in the aorta and to varying degrees in carotid arteries, the femoral arteries remain free of macroscopic plaque (observation in control animals). Only animals showing no cholesterol toxicity were included in the study, and no mortality was observed. Serum cholesterol levels obtained monthly averaged 1400 mg/dL across all animals. Detailed analyses and other blood biochemistries are shown in supplemental Figure I and supplemental Table I (available online at http://atvb.ahajournals. org). Anesthesia was induced with ketamine/xylazine (35/5 mg/kg IM) and continued with 1% to 3% isoflurane while the rabbits were mechanically ventilated. A 2F OTW Opensail angioplasty catheter (2 mmx8 mm, Guidant Corp) was aseptically inserted into the right carotid artery via a cut-down approach and fluoroscopically guided into the femoral artery. Thrombus formation in the catheter was prevented with heparin (150 U/kg). The catheter was positioned within the arterial segment and inflated 3 times to a pressure of 4, 5, and 6 atmospheres sequentially (30 second inflations with 60 second pauses in-between). In each rabbit, both femoral arteries were injured and the vessels were randomized to treatments and controls as outlined in Figure 1. Alphavβ3-targeted rapamycin nanoparticle emulsion (0.8 mL) or respective control was infused into the injured vessel lumen between vascular snares and allowed to incubate for 5 minutes. Next, unbound nanoparticle emulsion was aspirated from the lumen, and the vessel segment was flushed with saline (3x). Snares were then released, and blood flow was reestablished. Excisions were closed and the rabbits were transferred to a 1.5 T clinical MRI scanner for baseline MRI images and angiograms approximately 40 minutes later. After MRI, the rabbits were recovered from anesthesia and received routine postop care. Two weeks later a repeat MR angiogram of the femoral arteries was performed, followed by excision of the injured vessel segments for microscopic study.
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Magnetic Resonance Imaging
A 1.5 Tesla clinical MRI scanner (NT Intera CV, Philips Medical Systems) and techniques optimized to assess persistence of contrast enhancement and in vivo luminal dimensions throughout the injured vessels were used. Multislice T1-weighted, gradient-echo, time-of-flight angiograms of the femoral and iliac arteries of NZW rabbits were obtained using a 5-element phased array surface coil operating in the receive mode (repetition times [TR]=40 ms and echo times [TE]=4.6 ms). Imaging of the vascular wall was performed with T1-weighted, fat-suppressed, fast spin-echo (TSE) sequences (TR=532 ms, TE=11 ms, 250x250 µm in-plane, 2 mm slice thickness, echo train=4, number of signals averaged=8). Sliding radiofrequency saturation bands were placed proximally and distally to the region of image acquisition and moved with the selected imaging plane to ensure complete nulling of the blood signal.
Histology and Immunohistology
Femoral arteries were injected with OCT to preserve luminal diameter, excised and embedded in OCT, flash-frozen in liquid nitrogen (LN2), and stored at –80°C for further analysis. Injured vessels (1.5 cm segment) were sampled every 14 µm, and 7-µm sections were stained with hematoxylin and eosin (H&E) for histomorphometric analysis. Microscopic images were obtained with a Nikon E800 microscope using a Nikon DXM 1200 digital camera connected to a Dell Dimension 4100 computer using Nikon ACT-1 image capture software.
Histomorphometric measurements of lumen, intima, media, and total vessel area were obtained from the femoral artery segments: vβ3-targeted rapamycin nanoparticles (n=12 arteries); vβ3-targeted nanoparticles without drug (n=6 arteries); nontargeted rapamycin nanoparticles (n=8 arteries); and saline (n=12 arteries; Figure 1). Media was defined as the area between external elastic lamina (EEL) and the internal elastic lamina (IEL), neointima was defined as the area enclosed between the IEL and the lumen, and the neointima/media ratio was calculated from these measurements. Because we observed considerable variability in luminal areas throughout the injured vessel segments, we also estimated the percentage luminal stenosis using the formula neointima+lumen/lumen areax100.24–26
To assess endothelial healing, in a separate cohort of 29 animals, 58 femoral arterial segments were treated with vβ3-targeted nanoparticles with rapamycin (n=20), vβ3-targeted nanoparticles without drug (n=9), nontargeted rapamycin nanoparticles (n=9), or saline control (n=20; Figure 1). At days 1, 7, 14, and 28 animals were euthanized and the arteries excised, opened longitudinally, rinsed with buffered saline (leading to removal of red cells and unbound fibrin), and fixed with buffered formalin. For these estimates we developed a semiquantitative method to determine endothelial healing en face using Carstair’s stain to discriminate injured endothelium (fibrin deposition, red; disrupted intima/media, red/blue) versus uninjured cells (yellow-orange) at each time point (Figure 7A and 7B). The stained arterial segments were scanned en face with an Olympus BX61 microscope and areas quantitated with Olympus Micro Suite FIVE software (Olympus America) according to respective color.
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Statistical Analyses
All quantitative data were analyzed using the SAS using 1-way ANOVA with each iliac vessel segment defined as an experimental unit. Means for each treatment group were separated using the Least Significant Difference (LSD) method using an alpha level of P<0.05.
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Results |
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In Vitro Drug Dissolution
The retention of rapamycin in the nanoparticle surfactant under infinite sink conditions was assessed in dissolution studies. Rapamycin was highly retained in the lipid surfactant layer, with approximately 1% loss per day over 3 days (ie, 97% drug retention, Figure 2).
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Nanoparticle-Facilitated Drug Delivery
Femoral arteries of 6-month-old NZW rabbits, which had been fed a high-cholesterol diet to induce atherogenesis for 4 months, were randomized to local treatment with vβ3-targeted nanoparticles with 0.4 mol% rapamycin, with vβ3-targeted nanoparticles without drug, with nontargeted nanoparticles with 0.4 mol% rapamycin, or to saline for 5 minutes after balloon overstretch injury. Noninvasive MR imaging at 1.5 T demonstrated the presence of the integrin-targeted paramagnetic nanoparticles within the injured arterial wall segments 30 to 40 minutes after delivery and reestablishment of blood flow. T1-weighted black blood MR images of vascular segments exposed to vβ3-targeted paramagnetic nanoparticles, with or without drug, showed MR signal enhancement, whereas virtually no signal enhancement was detected after treatment with nontargeted paramagnetic nanoparticles or saline (Figure 3). These data confirmed the local intramural delivery and retention of vβ3-targeted nanoparticles into the stretch-fractured arteries.
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Inhibition of Stenosis After Balloon Injury
Baseline MR time-of-flight angiography within 60 minutes of angioplasty and treatment demonstrated patent arteries without luminal flow-obstruction or vascular wall dissection in all treatment groups (Figure 4A). Two weeks later, however, prominent vascular luminal irregularities were observed in vessels that had been exposed to vβ3-targeted nanoparticles without drug, to nontargeted nanoparticles with rapamycin, or to saline. In contradistinction, segments treated with vβ3-targeted rapamycin nanoparticles had minimal or no lumen irregularities detectable by MR angiograms (Figure 4B and 4C).
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For detailed analysis of stenosis severity and length, 38 femoral arteries were excised, and 7-µm sections were obtained and stained every 14 µm over the length of the injured segment and were microscopically examined. Bordering uninjured vasculature showed no pathological intimal thickening. However, neointimal proliferation was noted in all injured segments with the most significant plaque appreciated among the nondrug treated arteries (Figure 5).
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Microscopic morphometric assessment of neointima area and neointima/media ratio revealed that injured vessels treated with vβ3-targeted rapamycin nanoparticles had less plaque and stenosis than controls (Figure 6). Neointima area and neointima/media ratio of injured vessels treated with saline, targeted nanoparticles without drug, and nontargeted nanoparticles with rapamycin did not differ among treat-ments, 0.74 mm2±0.25 mm2 and 1.38±0.25, respectively. Alphavβ3-integrin-targeted rapamycin nanoparticles decreased (P<0.05) neointima area and neointima/media about 50% versus the controls, 0.45 mm2±0.18 mm2 and 0.73±0.12, respectively. Similarly, average and maximal vascular stenosis of injured vessels treated with saline, targeted nanoparticles without drug, and nontargeted nanoparticles with rapamycin did not differ among treatments, 23.2±2.3% and 49.3±2.9% respectively. Alphavβ3-integrin-targeted rapamycin nanoparticles decreased (P<0.05) the average and maximal stenosis levels by about 50% versus the controls, 14.1±2.6% and 27±6.7% respectively.
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Endothelial Healing Unaffected by Nanoparticle-Facilitated Drug Delivery
For detailed analysis of endothelial healing, femoral arteries from animals, which had been treated with vβ3-integrin-targeted nanoparticles with 0.4 mol% rapamycin (n=20), or from the 3 control groups (nontargeted nanoparticles with 0.4 mol% rapamycin [n=9], vβ3-integrin-targeted nanoparticles without drug [n=9], or saline [n=20]), were excised on postinterventional days 1, 7, 14, and 28. Endothelial integrity was analyzed using longitudinally opened en face preparations of the balloon injured vascular segment (area at risk) and processed with Carstair’s staining (Figure 7A). In vascular samples obtained 1 day after balloon injury, more than 80% of the endothelium in the area at risk was damaged. Gradual healing was observed over the subsequent 4-week time course. By week 4, the endothelium was healed in all arteries. No differences in the rate of endothelial healing were observed among arteries treated with vβ3-targeted rapamycin nanoparticles and any of the control groups (Figure 7C).
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Discussion |
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In these experiments, we have shown that local delivery of rapamycin with
vβ3-targeted perfluorocarbon nanoparticles into the balloon injured vascular wall inhibits stenosis with-out delaying endothelial healing. These findings illustrate the potential benefit of targeted nanoparticulate agents to deliver and to achieve the antirestenotic benefits of rapamycin in lesions that are not amenable to stent placement or in cases where implantation of nondrug eluting stents is preferred. Although not required for clinical application, the high paramagnetic contrast potential of these particles offered a unique tracking marker in the present study and could provide important information in the context of MRI interventional procedures. Restenosis is a multifaceted vascular complication of percutaneous transluminal angioplasty that involves arterial wall remodeling mainly through the production of extracellular matrix, and the activation, proliferation, and migration of vascular smooth muscle cells. Whereas the development of atherosclerotic plaque in native vessels is a heterogeneous process with involvement to differing degrees at different time points of macrophages, T-lymphocytes, smooth muscle cells, fibroblasts, etc, the (re-)stenosis response to balloon-angioplasty is largely attributable to activation of smooth muscle cells and vascular remodeling.
Before the success of drug-eluting stents, the local delivery of therapeutic agents directly into the injured vessel wall was explored to increase therapeutic concentrations relative to systemic administration with improved side-effect profiles. Those agents studied included vascular endothelial growth factor,27,28 corticosteroids,29,30 paclitaxel,31 urokinase,32,33 low-molecular-weight heparin,34 colchicine,35 methotrexate,36 and others. Some of these agents, particularly the hydrophobic antiproliferative drugs, showed benefit toward decreasing restenosis in animal models. However, each of these therapeutic regimens exposed the injured site to a marked excess of drug that was not retained within the vascular wall and migrated into downstream tissues with negative effects. Moreover, the residence of these agents at the intervention site was transient, and some even increased the ischemic event rates.33 To retain drug at the intervention site, a few investigators explored the utility of nontargeted drug encapsulation in more classical therapeutic delivery formulations.35,37,38 These systems, including biodegradable microcapsules, predominantly passed through the fractured vessels. Residual drug from particles passively entrapped in the lesions in some instances provided antirestenotic benefit the effects, but these technologies have not translated to the clinic. More recently, interest in small interfering RNA-mediated gene silencing of pathways in atherogenesis has developed.39,40 Furthermore, novel targets such as calcium/calmodulin-dependent protein kinases41 and direct factor Xa inhibitors42 are being investigated to inhibit restenosis.
Stent-based delivery of antiproliferative agents into the stretch-induced arterial wall has dramatically reduced clinically significant restenosis after coronary angioplasty by constraining drug release to the injured vascular segment.1–7 However, these DES are not suitable for all lesions and clinical situations, which requires the continued use of non-DES or angioplasty alone.
As demonstrated in this and earlier studies,16,17,43 perfluorocarbon nanoparticles can be functionalized and targeted to an array of cellular and extracellular vascular biomarkers after balloon injury. Intramural proteins, such as vβ3-integrin expressed by stretch-activated smooth muscle cells exposed along the sheared tissue planes of the arterial wall, provide ample targets for the drug-laden nanoparticles.43–45
MR angiography revealed that lesions treated locally with targeted rapamycin nanoparticles had less plaque formation and lumen occlusion 2 weeks later than similar vessel segments exposed to vβ3-integrin-targeted nanoparticles without drug or saline. Histological analysis confirmed the benefits of local rapamycin delivery versus the control lesions consistent with expectations derived from the published sirolimus stent experience.1,4,5,46
We hypothesize that the deposition of low concentrations of this chemotherapeutic agent within the wall and predominantly away from the healing endothelium may be the critical elements that allowed endothelial repair to progress at a natural rate. In summary, the data show that molecularly-targeted, nanoparticle-facilitated, locally constrained intramural delivery of rapamycin into injured vessels can reduce stenosis response and does not impede endothelial healing.
Limitations
In the present study, local intramural delivery was facilitated by vascular snare enclosures with the intent to eliminate systemic circulation of the rapamycin nanoparticles. Based on nanoparticle aspirate recovery the minute dosage of rapamycin deposited by the intramural nanoparticles was estimated to be 4 µg to 5 µg per vessel, which was about 30-fold less than the amount of rapamycin presented by eluting stents.47 We anticipate that vβ3-targeted nanoparticles could be infused into the site of balloon injury immediately after percutaneous angioplasty using a specifically-designed delivery catheter with a central lumen for continuous by-pass blood flow. Unfortunately, such catheter delivery systems were unavailable, but similar devices have been previously fabricated and marketed.
Although the effectiveness of vβ3-targeted rapamycin nanoparticles might be expected in conjunction with bare metal stents, this concept must be addressed and demonstrated in future studies. Minor adjustments in drug-loading may be required.
The hyperlipidemic NZW rabbit model elicits a hyperplasia response to balloon overstretch injury comparable to human angioplasty,48,49 but the histological features of these lesions are inconsistent with advanced atherosclerotic lesions as classified by the American Heart Association.50
Finally, the density of smooth muscle and other cells expressing vβ3-integrin in these rabbits may differ from human atherosclerotic plaque, which could alter the number of drug-laden nanoparticles retained. Evaluation of this agent in alternative animal models (eg, porcine) will be needed to support these findings.
Conclusion
In this study we have demonstrated that intramural delivery of vβ3-targeted nanoparticles with minute levels of rapamycin inhibited stenosis without delaying endothelial healing after balloon injury. In light of potential risks and cost-benefit concerns surrounding the use of drug eluting stents, alternative approaches to achieve the benefit of antirestenotic drug treatment while limiting the potential adverse effects should be explored. Alphavβ3-targeted rapamycin nanoparticles may be an alternative technology that could be implemented during clinical interventional procedures alone or in combination with follow-on bare metal stent placement.
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Acknowledgments |
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We thank Ralph W. Fuhrhop for assistance in producing the nanoparticle formulations.
Sources of Funding
We acknowledge grant support from the American Heart Association (0660028Z), the National Institutes of Health (HL-78631, HL-73646, NO1-CO-37007, and EB-01704), and Philips Medical Systems.
Disclosures
Dr Caruthers is an employee of Philips Medical Systems. Drs Lanza and Wickline are cofounders and shareholders of Kereos, Inc, St. Louis, Mo.
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Footnotes |
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Original received March 18, 2007; final version accepted January 31, 2008.
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