© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Local drug delivery systems and prevention of restenosis
Department of Cardiology and the Joseph J. Jacobs Center for Vascular Biology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk F-25, Cleveland, OH 44195, USA
* Corresponding author. Tel.: +1 216 4459490; Fax: +1 216 4459595; E-mail: topole@cesmtp.ccf.org
Received 11 February 1997; accepted 3 June 1997
KEYWORDS Restenosis; Percutaneous coronary revascularization
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1 Introduction |
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It is somewhat incongruous that the successful performance of percutaneous transluminal coronary revascularization, a technically challenging and somewhat delicate endeavour, is predicated on the delivery of a traumatic insult to the vascular wall. This injury incites a cascade of compensatory responses, involving thrombosis and inflammation, vascular smooth muscle proliferation and migration, and matrix production and deposition. Although this reparative process usually stabilizes the site of injury and ensures a successful long term result, in 30 to 50% of cases it is excessive [1], resulting in compromise of the lumen with the potential for recurrent ischemia.
Our understanding of the process of restenosis, although not yet complete, has evolved considerably in recent years. There is a complex interplay of vessel wall remodeling and neointimal proliferation. Remodeling refers to a contracture or ‘shrinkage’ of the vessel, primarily related to the inflammatory process in the vessel wall which involves the media and adventitia. The neointimal proliferative process appears to be linked to vascular smooth muscle cell activation, proliferation and migration [2, 3]. The deployment of an intracoronary stent at the site of injury, by providing a scaffold within the vessel wall, can reduce the impact of vascular remodeling, but may be accompanied by an exhuberant intimal hyperplastic response [4]with consequent restenosis in a persistent 20–30% of cases [5, 6].
Thus, over recent years there has been a widespread intensive research effort directed towards identifying pharmacotherepeutic regimens targeting primarily (but not exclusively) the smooth muscle cell, to prevent the neointimal restenotic process. These have involved conventional pharmacological agents, as well as novel gene therapies, and many of these have been found to be effective in preventing restenosis in animal models of vascular injury following systemic administration. However, when these agents have progressed to clinical trials, the results have been almost universally disappointing [1].
The concept of local drug delivery was spawned by the observation that many of the therapies successfully tested in animal models were only effective at doses far greater than could safely be applied to patients. It was postulated that by confining the therapeutic agent to the site of injury, greater local concentrations could be achieved with reduced potential for systemic toxicity. Several elegant animal studies provided validation of this hypothesis, however, the successful translation of this to a viable clinical strategy has been technically challenging. Major obstacles that have been encountered include: (1) the design of devices that enable delivery of adequate quantities of drug to the vessel wall without either injuring the wall or compromising flow, (2) the development of delivery vehicles that allow retention of the administered drug within the local environment for periods of time adequate to ensure a therapeutic effect, (3) the optimization of strategies enabling the transfer of genetic material into cells within the vessel wall, and (4) the development of sustained delivery polymeric coatings for stents that do not produce thrombosis or an inflammatory tissue response.
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2 Validation of the concept of local drug delivery |
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Some of the most insightful work in the area of pharmacotherapy for the prevention of restenosis has been provided by Edelman et al., focusing on the antithrombotic and antiproliferative agent heparin. Clinical trials of this agent had surprisingly shown it to have little impact, or even increase the incidence of restenosis relative to placebo in patients undergoing coronary angioplasty [7, 8]. In a rat model of vascular injury, Edelman et al. showed that heparin administered subcutaneously at doses (1 mg/kg) and time intervals comparable to those used in clinical trials, exacerbated rather than alleviated intimal hyperplasia. However, both a continuous infusion of a larger dose (7.2 mg/kg/day), or perivascular administration of heparin via a surgically implanted polymeric device, significantly reduced the degree of both intimal hyperplasia and intimal cell proliferation (Fig. 1), supporting the contention that pharmacokinetic considerations, in part, may explain the disparity between animal model data and clinical trial experience [9]. In addition, in contrast to intermittent subcutaneous administration, neither continuous intravenous infusion nor the local delivery of heparin prolonged the activated partial thromboplastin time, indicating that it was possible for a local beneficial effect to be uncoupled from unwanted systemic side effects. Further evidence supporting the ability of locally delivered agents to impact upon restenosis was provided by Villa et al. who periadventitially wrapped dexamethasone impregnated silicone polymers around the carotid arteries of rats undergoing balloon injury [10]. Neointimal proliferation was significantly reduced in animals implanted with the glucorticoid-releasing polymer relative to those receiving placebo. Among those receiving active treatment, there was a 2-fold reduction in neointimal hyperplasia at sites covered by silicone matrices compared to the non-covered arterial segments. Therefore, although the effect of the drug was not exclusively site specific, the local delivery of dexamethasone had an incremental impact on neointimal proliferation relative to systemically absorbed drug (Table 1).
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Periadventitial delivery systems are ideally suited for small animal research, and may allow the identification of agents that inhibit neointimal proliferation at sites of local delivery after vascular injury [11]. In addition, they may be of value in certain clinical situations such as restenosis occurring within the venous limb of A–V shunts in hemodialysis patients. Because the stimulus for venous neointimal hyperplasia is prolonged (i.e., pressure transmitted from the arterial circulation), sustained release of a drug is desirable and an appropriate drug-containing film can be directly applied to the extravascular surface when the shunt is installed. However, such systems are clearly less appropriate for preventing coronary restenosis. Accordingly, a number of devices have been devised that permit percutaneous, transcoronary application of local therapy at the time of coronary intervention.
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3 Local delivery devices (Table 2) |
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3.1 Balloon catheter delivery systems
3.1.1 Double balloon (Fig. 2a)
The earliest approach to percutaneous local drug delivery involved the use of a double balloon catheter [12]. This device is passed over a guidewire like a conventional angioplasty balloon, the dual balloons are inflated proximal and distal to the site of injury, and drug is infused into the isolated vessel segment between the two balloons. Infusion pressures of 300 mmHg are sufficient for the uptake of agent into the arterial wall without causing local trauma [13]and the device has been used to deliver both pharmacologic agents and genetic material in a variety of animal models [12, 14]. However it suffers from a number of significant limitations: adequate drug delivery in vivo requires inflation times of 15 to 30 min resulting in substantial distal ischemia; the length of the enclosed chamber results in the loss of some drug into side branches when used in the coronary vasculature, and the balloon inflation pressures necessary to seal the compartment may cause additional vessel injury proximal and distal to the target site.
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3.1.2 Porous and microporous balloons (Fig. 2b,c).
The standard porous balloon was developed to overcome some of the deficiencies associated with the double-balloon catheter described above [15]. Inflation of a non-compliant balloon containing pores of 25 µm in diameter results in direct delivery of infusate through the pores into the juxtapositioned arterial wall with the depth of penetration directly related to the perfusion pressure (usually between 2 and 5 mm Hg). The major drawback of this device is the potential for vascular barotrauma caused by the fluid jets [16]. This not only results in potential immediate local complications, but may also increase the likelihood of a long-term neointimal response [17]. In normal porcine coronaries, this injury can be minimized by reducing both the volume and pressure of delivery of infusate, without compromising delivery of solute into the vessel wall [18], but it is not clear whether the same is true in atherosclerotic human vessels.
The microporous balloon is a modification of the above, consisting of an inner balloon with an array of 25 µm holes surrounded by an outer membrane with 0.8 µm pores [16]. Although the inflation pressures are comparable to those with the porous balloon (2 to 5 atm), the infusate weeps from the pores in the external membrane, reducing the potential for tissue injury.
The porous and microporous balloon designs share some important limitations. Because both rely on hydrostatic pressure to both to inflate the balloon and infuse the contents of the catheter, significant systemic administration of the solute may occur during balloon inflation and deflation. In addition, the holes in both can become obstructed, resulting in nonhomogeneous solute delivery.
3.1.3 Channel, transport and sheath balloons (Fig. 2d)
Several delivery catheters have been designed with the aim of dissociating drug infusion pressure from that required for balloon inflation. The channel catheter (Boston Scientific Corp) consists of a central balloon surrounded by a series of channels, each with a single 100 µm hole through which the drug can be infused [19]. The Transport coronary angioplasty catheter (Cardiovascular Dynamics) is similar, with a central balloon surrounded by an outer porous balloon for drug infusion [20]. Both these catheters simplify the procedure of post angioplasty local drug delivery allowing the intervention and subsequent pharmacotherapy to be performed sequentially with the same device. Another novel variation consists of an infusion sheath (Infusion Sleeve, Localmed, Inc.) which can be advanced over any standard angioplasty catheter and advanced to the lesion after balloon dilatation [21].
3.1.4 Hydrogel balloon
The hydrogel coated balloon (Boston Scientific Corp) is designed to enable simultaneous lesion dilatation and local delivery [22]. The hydrophilic acid polymer coating has a thickness of 5 to 20 µm when dry and swells by a factor of 3 when exposed to an aqueous solution that may include drugs or genetic material. A thin layer of therapeutic agent is coated onto the balloon, allowed to dry and then ‘pressed’ into the vessel wall during balloon inflation. Disadvantages of the Hydrogel catheter include its relatively limited drug carrying capacity, and the fact that the drugs are rapidly washed off the balloon on entry into the blood stream, necessitating the application of an effective but somewhat cumbersome protective sheath over the balloon as it is advanced toward the target vessel.
3.1.5 Dispatch catheter (Fig. 2e)
The dispatch catheter (Scimed Life Systems Inc.) consists of an outer helix-shaped infusion balloon with delivery channels that when inflated allows prolonged contact of infusate with the arterial wall in the inter-helical spaces [23]. Distal coronary perfusion is maintained via a central lumen, allowing periods of infusion in excess of 30 to 60 min without causing coronary ischemia. A theoretical disadvantage of this catheter is that the presence of the inflated helical balloon during drug delivery may prevent homogeneous infiltration of solute into the vessel wall. The dispatch catheter has been approved by the Food and Drug Administration in the United States for intracoronary drug infusion.
3.1.6 Mechanical delivery
The iontophoretic balloon relies on an electic current to increase cell permeability and facilitate transport into the vessel wall. The catheter consists of a porous balloon containing the cathode which is advanced across the lesion, and the anode, placed on the skin, is activated with a small electic charge. One preliminary study has shown iontophoresis to result in significantly greater delivery efficiency than obtained by passive diffusion, with minimal vessel wall trauma [24]. A second mechanical delivery system that is undergoing preliminary investigation consists of a catheter with circumferential injection needles, allowing direct application of therapeutic agent into the adventitia where it may persist for weeks after injury. Despite its invasive nature, this device is reported to cause minimal local trauma and no long term intimal hyperplasia [25].
3.1.7 Choice of balloon catheter delivery system
The optimal local delivery device should be simple to use, result in the greatest deposition of drug in the vessel wall without causing local trauma, distal ischemia or systemic administration. On theoretical grounds, both the microporous balloon and those which differentiate inflation from perfusion pressures most closely meet these criteria, although the prolonged dwell times achievable with the Dispatch catheter may prove particularly desirable. It should be noted that many of the delivery systems are in a continuing state of evolution and as they become optimized, well controlled studies comparing various catheter based drug delivery strategies will become imperative.
3.2 Limitations of balloon catheter delivery systems.
3.2.1 Delivery efficiency
Despite the plethora of devices developed to optimize the process of local drug delivery, delivery efficiency, that is the fraction of agent which leaves the catheter and is deposited in the vessel wall, is generally less than 1% [26, 27]. However, this still results in a local concentration several hundred fold greater than that in the systemic circulation. In atherosclerotic vessels which have undergone antecedent angioplasty, deposition is into the dissection planes and into side branches and microvasculature. Direct deposition into the intima and media is rarely observed, potentially a major limitation of local drug delivery, however since smooth muscle cell proliferation occurs in areas of arterial dissection, the deposition of active agent at these sites presumably impacts on the restenotic process.
3.2.2 Retention of infused drug
Agents introduced into the vessel wall by local catheter delivery systems may be rapidly washed out over minutes to hours, particularly if they have no specific intramural binding properties [28]. While the issue of retention may not be important for agents like oligonucleotides that permanently affect cell cycle regulation (see below), agents that do not exhibit cell binding properties may be eliminated before they can exert a biologically relevant effect. A number of controlled release matrices have been developed with the goal of prolonging drug residence times within the vessel wall. Most consist of microparticles composed of biodegradable polymers which can be impregnated with drug and are small enough to be administered percutaneously. Once in the vessel wall, the size of the microparticle (5 to 15 µm) prevents elution, and the agent is gradually released. Polymeric microparticles appear capable of dramatically increasing drug residence times, but they may incite an inflammatory response [29]. This may be prevented by reducing the size of the particle, without significantly compromising the retention properties of the compound [30].
3.2.3 Efficiency of gene transfer
Retention of a product may not be so critical for genetic material which, when taken up by vascular cells, may provide prolonged local expression of their products. In order to be effective, a gene must transfect its host cell, so strategies to optimize gene transfer are important components of efficient local delivery systems. A number of gene transfer vectors have been associated with successful in vivo vascular gene transfer, including plasmid DNA alone, plasmid DNA with liposomes, retroviral vectors and adenoviral vectors (Table 3).
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Of these, replication defective adenoviruses have resulted in the greatest transfection efficiency, being capable of transfecting 20 to 30% of susceptible cells [31, 32]. This vector has been used to successfully transfect a number of genes into different animal models with a salutatory effect on the restenotic process. For example the GAX (growth arrest homeobox) gene encodes transcription factors that maintain the non-proliferative phenotype of vascular smooth muscle cells. The adenovirus mediated local delivery of this gene to denuded rat carotid arteries was shown to significantly reduce neointimal hyperplasia [33]. Similarly, the introduction of the gene encoding the cell cycle inhibitor, cyclin dependent kinase inhibitor CKI p21 via the same vector, resulted in a significant reduction in neointimal formation in a similar animal model [34]. The enzyme herpes simplex thymidine kinase phosphorylates a nucleoside analogue gancyclovir, which is capable of killing dividing cells. In a number of animal models, adenoviral transfer of the gene encoding this enzyme coupled with gancyclovir administration was associated with inhibition of vascular cell proliferation and reduction of neointimal development [35, 36]. The retinoblastoma gene product (Rb) inhibits cell proliferation without cytotoxicity in many mammalian cell types and an adenovirus encoding for an active form of Rb was transferred into injured rat carotid and porcine iliac arteries, resulting in decreased neointimal formation [37]. Adenoviral vectors are however highly infectious for a variety of organs, including liver and brain [38, 39], and may therefore result in systemic expression of the transgene. They may also incite inflamatory and immune responses [40]. Efforts have been made to modified adenoviruses to reduce their potential toxicity, and second generation products are being evaluated [41].
Transfection efficiency of plasmid DNA with liposomes may be significantly augmented by incorporating inactivated viral particles [42]. This strategy has been used to deliver cDNA encoding endothelial cell nitric oxide synthase to the vessel wall in balloon injured rat carotids [43]. The transfected vessels expressed comparable levels of NO to uninjured arteries and this was accompanied by a 70% reduction in neointimal formation, reflecting the ability of NO to inhibit smooth muscle cell migration and proliferation. Additional strategies to optimize gene transfer undergoing investigation include the inclusion of tissue specific endogenous promoters, allowing gene expression to be restricted to certain cell types within the arterial segment at the time of transfection.
One somewhat cumbersome approach to gene therapy is to seed the vasculature with cells that have been transfected with the desired gene. Using a double balloon catheter, vascular smooth muscle cells have been implanted into denuded iliofemoral artery segments of pigs in vivo [44], but this has not yet been accomplished in the coronary circulation.
Another promising technique involves the introduction of antisense oligonucleotides into a cell in order to inactivate the mRNA encoding proteins important in the restenotic process. These oligonucleotides comprise short synthetic segments of DNA designed to hybridize with the RNA of interest, preventing its translation. Successful in vivo studies have been reported using antisense oligonucleotides directed against c-mbc and c-myb (nuclear transcription factors), and proliferating cell nuclear antigen and cell cycle specific proteins cdc2 and cdk2 kinases [11, 45–47]. Recent studies have suggested the antisense oligonucleotide may exert their activity through non-antisense mechanisms [48], possibly by binding non-target m-RNA and preventing its translation. In addition, the oligonucleotide may be capable of binding intracellular proteins and changing their functional characteristics. The implications of this require further evaluation before this strategy will reach the stage of clinical application.
3.3 Stents
Scaffolding a coronary artery at the site of balloon injury with a stainless steel stent, prevents compensatory vessel wall remodeling and thus eliminates one of the contributing factors toward restenosis. A number of strategies have been developed in order to simultaneously target both neointimal hyperplasia and vessel wall remodeling. Considerable effort has been directed towards developing stents coated with a biodegradable-drug-impregnated polymer, capable of gradually releasing therapeutic agents into the vessel wall. Realizing this goal has been difficult, as a number of polymers, although biocompatible in other settings, excite an extensive inflammatory response when implanted in porcine coronary arteries [49, 50]. Recently however, several polymers, such as poly-L-lactic acid, fibrin and a polyamine-dextran sulphate trilayer have shown some promise [51–53]. In the recent Benestent II pilot study, implantation of a polyamine-dextran sulphate coated stent to which heparin was covalently bound in 207 patients was associated with an overall 6 month restenosis rate of 13% [54]. Strictly speaking, this strategy did not involve local drug delivery, as the polymer was non-eluting so the heparin remained attached to the stent, and it is not clear whether the low incidence of lesion recurrence was affected by patient selection, the technique for stent deployment, or the heparin coating [55]. More recently, the reported success of the application of local radiation at the time of PTCA in the prevention of restenosis (see below) has indicated that there is an early window of opportunity to impact upon this process. Therefore, the goals of future drug delivery protocols involving polymeric films applied to stents should incorporate early, short term exposure of moderately high doses as a part of the overall strategy. Sustained release over a long period of time should be avoided if the drug is toxic to the medial or adventitial cells or delays re-endothelialization.
Concerns about biocompatibility of the drug eluting polymers, together with early (what now appears to be largely unfounded) suspicions that long-term implantation of metallic stents could be accompanied by a chronic inflammatory response with adverse local sequelae, prompted development of a coated removable stent. Composed of a nitinol alloy that deploys on cooling and collapses on heating to 55°C, this stent is capable of local drug delivery, but further studies are required to ensure that removal of this device in vivo after drug delivery is not associated with thermal injury [56].
Another theoretical approach to combined stenting-local delivery involves seeding stents with cells engineered to secrete biological products that may impact on the restenotic process. Although genetically engineered endothelial cells have been successfully grown on stents, their purchase appears somewhat precarious, and they are readily sheared off by balloon inflation [57]. So far, in vivo application of this strategy has not been reported.
3.4 Local radiation
Interest in the use of local radiation therapy for the prevention of restenosis was precipitated by the observation a number of benign fibroproliferative disorders that histologically share characteristics with the neointimal hyperplastic response, respond favorably to low doses of ionizing radiation. Encouraging results have now been reported by a number of investigators using catheter-based systems to deliver low dose endovascular radiation in a range of animal models of vascular injury [58–60]. Sources of both gamma and beta radiation have been used although experience to date has been most extensive with the former. Regardless of the source of radiation, the doses required (<20 Gy) are less than 25% those used normally for treatment of malignancies.
A number of preliminary clinical studies are underway investigating the use of endocoronary irradiation in patients [61]. The largest of these, the SCRIPPS study, has compared two doses of gamma radiation delivered on an iridium 192 guidewire with control treatment in 55 patients with restenotic lesions following coronary angioplasty. Although the early data from this trial have been encouraging, complete follow-up is awaited.
There are several limitations associated with catheter-based endovascular radiation therapy, including excessive radiation when a gamma source is used, and difficulties ensuring uniform dosimetry at all levels of the vessel wall, particularly when there is an eccentric residual lesion. Radioactive beta-particle emitting stents may overcome some of these disadvantages, while at the same time providing protection against remodeling process. Preliminary encouraging data have been reported in several animal models using radioactive stents to prevent restenosis [62–64], although further studies are required to ensure that the effect on neointimal proliferation is both predictable and sustained before these devices will progress to the stage of clinical trials.
3.5 Future directions
It is perhaps inevitable that our lack of understanding of the complex processes responsible for restenosis, resulted in a ‘shotgun’ approach to research into its prevention. The plethora of local drug delivery devices, vehicles, and therapies together with the complete absence of standardized data to allow rational comparison between strategies reflects this. As we gradually tease out the mechanisms responsible for the restenotic process, so too should our preventative strategies become more rational. From the point of view of local drug delivery, deciding on optimal therapy may require careful comparison of risk/benefit profiles between different balloon and stent delivery systems, polymer particles of different sizes and characteristics and other novel vectors to enhance delivery efficiency, and between the different vectors for gene therapy. Given the fact that the consistent failure of systemic pharmacotherapy to impact on the restenotic process is, in many instances, likely due to inadequate tissue concentration of biologically active agent, we believe that local vascular delivery will evolve as a vital component of the armamentarium used to prevent restenosis. It will doubtless add to the initial cost of the interventional procedure, but should enhance the ability to achieve a successful long-term result following percutaneous coronary revascularization.
Time for primary review 38 days.
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