Nanoparticulate carriers for the treatment of coronary restenosis

The current treatment for coronary restenosis following balloon angioplasty involves the use of a mechanical or a drug-eluting stent. Despite the high usage of commercially-available drug-eluting stents in the cardiac field, there are a number of limitations. This review will present the background ofrestenosis, go briefly into the molecular and cellular mechanisms of restenosis, the use of mechanical stents in coronary restenosis, and will provide an overview of the drugs and genes tested to treat restenosis. The primary focus of this article is to present a comprehensive overview on the use of nanoparticulate delivery systems in the treatment of restenosis both in-vitro and in-vivo. Nanocarriers have been tested in a variety of animal models and in human clinical trials with favorable results. Polymer-based nanoparticles, liposomes, and micelles will be discussed, in addition to the findings presented in the field of cardiovascular drug targeting. Nanocarrier-based delivery presents a viable alternative to the current stent based therapies.     

药物涂层球囊概述及其在外周动脉疾病治疗中的应用进展

经皮经腔血管成形术(PTA)已广泛用于外周动脉疾病(PAD)的治疗。然而,该技术存在血管壁弹性回缩和内膜增生等不足。PTA术后植入金属裸支架(BMS)虽然可以减少血管壁弹性回缩,但由此引起的支架内再狭窄(ISR)又成为治疗中的一个突出问题。药物洗脱支架(DES)被用来解决狭窄问题,但晚期支架内血栓形成(LST)、内皮化延迟和必须长期抗血小板治疗等问题也随之而来。在这样的背景下,药物涂层球囊(DCB)获得了快速发展。DCB作为非支架方案,可将所携载的活性药物转移至病变段血管壁,对ISR或原发病变均有较好的治疗效果。本文简要介绍了DCB的发展历史,并通过实验室研究、动物实验和临床试验,从机制上阐述涂层技术、涂层药物、赋形剂等对DCB功效和安全性的影响以及DCB在PAD治疗中的应用进展。     

Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix

Today the most popular approach for the prevention of the restenosis consists in the use of the drug eluting stents. The stent acts as a source of drug, from a coating or from a reservoir, which is transported into and through the artery wall. In this study, the behaviour of a model of a hydrophilic drug (heparin) released from a coronary stent into the arterial wall is investigated. The presence of the specific binding site action is modelled using a reversible chemical reaction that explains the prolonged presence of drug in the vascular tissue. An axi-symmetric model of a single stent strut is considered. First an advection–diffusion problem is solved using the finite element method. Then a simplified model with diffusion only in the arterial wall is compared with: (i) a model including the presence of reversible binding sites in the vascular wall and (ii) a model featuring a drug reservoir made of a degradable polymeric matrix. The results show that the inclusion of a reversible binding for the drug leads to delayed release curves and that the polymer erosion affects the drug release showing a quicker elution of the drug from the stent.     

Optimization of Cardiovascular Stent against Restenosis: Factorial Design-Based Statistical Analysis of Polymer Coating Conditions

The objective of this study was to optimize the physicodynamic conditions of polymeric system as a coating substrate for drug eluting stents against restenosis. As Nitric Oxide (NO) has multifunctional activities, such as regulating blood flow and pressure, and influencing thrombus formation, a continuous and spatiotemporal delivery of NO loaded in the polymer based nanoparticles could be a viable option to reduce and prevent restenosis. To identify the most suitable carrier for S-Nitrosoglutathione (GSNO), a NO prodrug, stents were coated with various polymers, such as poly (lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL), using solvent evaporation technique. Full factorial design was used to evaluate the effects of the formulation variables in polymer-based stent coatings on the GSNO release rate and weight loss rate. The least square regression model was used for data analysis in the optimization process. The polymer-coated stents were further assessed with Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy analysis (FTIR), Scanning electron microscopy (SEM) images and platelet adhesion studies. Stents coated with PCL matrix displayed more sustained and controlled drug release profiles than those coated with PLGA and PEG. Stents coated with PCL matrix showed the least platelet adhesion rate. Subsequently, stents coated with PCL matrix were subjected to the further optimization processes for improvement of surface morphology and enhancement of the drug release duration. The results of this study demonstrated that PCL matrix containing GSNO is a promising system for stent surface coating against restenosis.     

Biodegradable stents as a platform to drug loading

Despite technical and mechanical improvement in coronary stents the incidence of restenosis caused by in-stent neointimal hyperplasia remains high. Oral administration of numerous pharmacological agents has failed to reduce restenosis after coronary stenting in humans, possibly owing to insufficient local drug concentration. Therefore, drug-eluting stents were developed as a vehicle for local drug administration. The authors developed a new drug-eluting polymer stent that is made of poly-l-lactic acid polymer mixed with tranilast, an anti-allergic drug that inhibits the migration and proliferation of vascular smooth muscle cells induced by platelet-derived growth factor and transforming growth factor->1. Polymer stents might be superior to polymer-coated metallic stents as local drug delivery stents in terms of biodegradation and the amount of loaded drug. Drug-mixed polymer stents can be loaded with a larger amount of drug than can drug-coated metallic stents because the polymer stent struts can contain the drug. Clinical application is required to assess the safety and efficacy of drug-eluting polymer stents against stent restenosis.     

载基因洗脱支架防治再狭窄的研究进展

药物洗脱支架(DES)在冠状动脉疾病的治疗中起到巨大作用,不但能机械支撑血管狭窄区,而且可以通过持续释放药物显著降低病灶处再狭窄率。然而,长期临床研究表明,载药DES在后期有引发血栓的风险。在DES表面载入基因药物,通过表面涂层输送系统局部缓慢释放治疗基因,能针对引起再狭窄的细胞过程进行修改。选择合适的治疗基因,可以抑制内膜增生,促进再内皮化,提高洗脱支架的有效性和安全性,是非常有前途的抗再狭窄方法。同时,良好的涂层材料不仅改善了支架表面的生物相容性,更能通过不同的基因药物输送系统有效控制治疗基因的释放速率。本文首先介绍了一部分针对再狭窄的治疗基因,在此基础上,综合阐述了基因缓释系统中使用的材料和技术,分析提炼了基因缓释系统的释放机理,举例分析了载基因洗脱支架的研究进展,并展望了该领域的发展前景。     

Efficiency of endovascular re-interventions for evolving restenosis of different types of stents

The paper compares the results of different treatment options (balloon angioplasty and restenting) for in-stent restenosis in case of evolving restenosis of drug- and nondrug eluting stents. The investigation enrolled 496 coronary heart disease patients with clinical presentation of angina pectoris and/or signs of myocardial ischemia, as well as hemodynamic restenosis of a previously implanted stent. Of them, 216 and 280 patients had restenosis of previously implanted drug- and nondrug-eluting stents, respectively. In the patients with non-drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis were significantly more frequently observed after balloon dilatation than after drug-eluting stent implantation (28.4 and 10.2%; p < 0.05; 19.9 and 8.7%; p < 0.05). In those with drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis did not differ significantly between balloon dilatation of restenosis and implantation of a second drug-eluting stent.     

Current perspectives of biodegradable drug-eluting stents for improved safety

The introduction of the drug-eluting stent (DES) proved to be an important step forward in reducing the rates of restenosis and target lesion revascularization after percutaneous coronary intervention (PCI). However, the rapid implementation of DES in standard practice and the expansion of the indications for PCI to high-risk patients and complex lesions also introduced a new problem. DES in-stent restenosis (ISR) occurs in 3 ?? 20% of patients, depending on the patient, lesion characteristics and the DES type. The initial commercially available DES used a stainless steel platform coated with a permanent polymer to provide a controlled release of an anti-restenotic drug. The platform, polymer and drug are all targets for improvement. More advanced metallic and fully biodegradable stent platforms are currently under investigation. The permanent polymer coating, a likely contributor to adverse events, is being superseded by biocompatible and bioabsorbable alternatives. New drugs and drug combinations are also a research goal, as interventional cardiologists and the industry strive towards a safer anti-restenotic DES. This paper reviews the benefits, risks, and current status of biodegradable drug-eluting stents.     

Effect of stent coating alone on in vitro vascular smooth muscle cell proliferation and apoptosis

Synthetic polymers, like methacrylate (MA) compounds, have been clinically introduced as inert coatings to locally deliver drugs that inhibit restenosis after stent. The aim of the present study was to evaluate the effects of MA coating alone on vascular smooth muscle cell (VSMC) growth in vitro. Stainless steel stents were coated with MA at the following doses: 0.3, 1.5, and 3 ml. Uncoated/bare metal stents were used as controls. VSMCs were cultured in dishes, and a MA-coated stent or an uncoated bare metal stent was gently added to each well. VSMC proliferation was assessed by bromodeoxyuridine (BrdU) incorporation. Apoptosis was analyzed by three distinct approaches: 1) annexin V/propidium iodide fluorescence detection; 2) DNA laddering; and 3) caspase-3 activation and PARP cleavage. MA-coated stents induced a significant decrease of BrdU incorporation compared with uncoated stents at both the low and high concentrations. In VSMCs incubated with MA-coated stents, annexin V/propidium iodide fluorescence detection showed a significant increase in apoptotic cells, which was corroborated by the typical DNA laddering. Apoptosis of VSMCs after incubation with MA-coated stents was characterized by caspase-3 activation and PARP cleavage. The MA-coated stent induced VSMC growth arrest by inducing apoptosis in a dose-dependent manner. Thus MA is not an inert platform for eluting drugs because it is biologically active per se. This effect should be taken in account when evaluating an association of this coating with antiproliferative agents for in-stent restenosis prevention.     

Numerical modelling of mass transport in an arterial wall with anisotropic transport properties

Coronary artery disease results in blockages or narrowing of the artery lumen. Drug eluting stents (DES) were developed to replace bare metal stents in an effort to combat re-blocking of the diseased artery following treatment. The numerical models developed within this study focus on representing the changing trends of drug delivery from an idealised DES in an arterial wall with an anisotropic ultra-structure. To reduce the computational burden of solving coupled physics problems, a model reduction strategy was adopted. Particular focus has been placed upon adequately modelling the influence of strut compression as there is a paucity of numerical studies that account for changes in transport properties in compressed regions of the arterial wall due to stent deployment. This study developed an idealised numerical modelling framework to account for the changes in the directionally dependent porosity and tortuosities of the arterial wall as a result of radial strut compression. The results show that depending on the degree of strut compression, trends in therapeutic drug delivery within the arterial wall can be either increased or decreased. The study highlights the importance of incorporating compression into numerical models to better represent transport within the arterial wall and suggests an appropriate numerical modelling framework that could be utilised in more realistic patient specific arterial geometries.     

Geometry parameterization and multidisciplinary constrained optimization of coronary stents

Coronary stents are tubular type scaffolds that are deployed, using an inflatable balloon on a catheter, most commonly to recover the lumen size of narrowed (diseased) arterial segments. A common differentiating factor between the numerous stents used in clinical practice today is their geometric design. An ideal stent should have high radial strength to provide good arterial support post-expansion, have high flexibility for easy manoeuvrability during deployment, cause minimal injury to the artery when being expanded and, for drug eluting stents, should provide adequate drug in the arterial tissue. Often, with any stent design, these objectives are in competition such that improvement in one objective is a result of trade-off in others. This study proposes a technique to parameterize stent geometry, by varying the shape of circumferential rings and the links, and assess performance by modelling the processes of balloon expansion and drug diffusion. Finite element analysis is used to expand each stent (through balloon inflation) into contact with a representative diseased coronary artery model, followed by a drug release simulation. Also, a separate model is constructed to measure stent flexibility. Since the computational simulation time for each design is very high (approximately 24?h), a Gaussian process modelling approach is used to analyse the design space corresponding to the proposed parameterization. Four objectives to assess recoil, stress distribution, drug distribution and flexibility are set up to perform optimization studies. In particular, single objective constrained optimization problems are set up to improve the design relative to the baseline geometry—i.e. to improve one objective without compromising the others. Improvements of 8, 6 and 15% are obtained individually for stress, drug and flexibility metrics, respectively. The relative influence of the design features on each objective is quantified in terms of main effects, thereby suggesting the design features which could be altered to improve stent performance. In particular, it is shown that large values of strut width combined with smaller axial lengths of circumferential rings are optimal in terms of minimizing average stresses and maximizing drug delivery. Furthermore, it is shown that a larger amplitude of the links with minimum curved regions is desirable for improved flexibility, average stresses and drug delivery.     

Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix

Today the most popular approach for the prevention of the restenosis consists in the use of the drug eluting stents. The stent acts as a source of drug, from a coating or from a reservoir, which is transported into and through the artery wall. In this study, the behaviour of a model of a hydrophilic drug (heparin) released from a coronary stent into the arterial wall is investigated. The presence of the specific binding site action is modelled using a reversible chemical reaction that explains the prolonged presence of drug in the vascular tissue. An axi-symmetric model of a single stent strut is considered. First an advection-diffusion problem is solved using the finite element method. Then a simplified model with diffusion only in the arterial wall is compared with: (i) a model including the presence of reversible binding sites in the vascular wall and (ii) a model featuring a drug reservoir made of a degradable polymeric matrix. The results show that the inclusion of a reversible binding for the drug leads to delayed release curves and that the polymer erosion affects the drug release showing a quicker elution of the drug from the stent.     

Development of new RNAi therapeutics

RNAi-mediated gene inactivation has become a cornerstone of the present day gene function studies that are the foundation of mechanism and target based drug discovery and development, which could potentially shorten the otherwise long process of drug development. In particular, the coming of age of "RNAi drug" could provide new promising therapeutics bypassing traditional approaches. However, there are technological hurdles need to overcome and the biological limitations need to consider for achieving effective therapeutics. Major hurdles include the intrinsic poor pharmacokinetic property of siRNA and major biological restrictions include off-target effects, interferon response and the interference with endogenous miRNA. Recent innovations in nucleic acid chemistry, formulations and delivery methods have gradually rendered it possible to develop effective RNAi-based therapeutics. Careful design based on the newest RNAi/miRNA biology can also help to minimize the potential tissue toxicity. If successful with systemic application, RNAi drug will no doubt revolutionize the whole drug development process. This review attempts to describe the progress in this area, including applications in preclinical models and recent favorable experience in a number of human trials of local diseases, along with the discussion on the potential limitations of RNAi therapeutics.     

Factors that affect mass transport from drug eluting stents into the artery wall

Coronary artery disease can be treated by implanting a stent into the blocked region of an artery, thus enabling blood perfusion to distal vessels. Minimally invasive procedures of this nature often result in damage to the arterial tissue culminating in the re-blocking of the vessel. In an effort to alleviate this phenomenon, known as restenosis, drug eluting stents were developed. They are similar in composition to a bare metal stent but encompass a coating with therapeutic agents designed to reduce the overly aggressive healing response that contributes to restenosis. There are many variables that can influence the effectiveness of these therapeutic drugs being transported from the stent coating to and within the artery wall, many of which have been analysed and documented by researchers. However, the physical deformation of the artery substructure due to stent expansion, and its influence on a drugs ability to diffuse evenly within the artery wall have been lacking in published work to date. The paper highlights previous approaches adopted by researchers and proposes the addition of porous artery wall deformation to increase model accuracy.     

Stents Eluting 6-Mercaptopurine Reduce Neointima Formation and Inflammation while Enhancing Strut Coverage in Rabbits

Background

The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface.

Methods

Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 μg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions.

Results

Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27^Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation.

Conclusion

We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.     

Drug-eluting stents: from bench to bed

The introduction of stents to clinical practice in 1987 was the major breakthrough in the field of percutaneous coronary intervention (PCI). The use of stenting has drastically improved the outcomes of traditional PCI. First stents were approved for bailout and treatment of dissections, reducing dramatically the need for emergent coronary artery bypass grafting (CABG) as a result of vessel closure during PCI. Later stents were proven to reduce the restenosis rate of PCI from 30%-40% with balloon angioplasty to 15%-20% with stents, primarily by eliminating elastic recoil and vascular remodeling as shown by intravascular ultrasound (IVUS) studies. These outcomes have led to a wide acceptance of stenting as the strategy of choice for more than 80% of all PCI procedures performed. The current review focuses on the following topics: (1) strategies in drug selection to reduce neointimal proliferation, (2) stent designs and polymer selection as a platform for drug-eluting stents, (3) review of major preclinical and clinical experimental work performed in the field, and (4) a discussion of the potential and limitations of the technology.     

Cardiovascular stent design and vessel stresses: a finite element analysis

Intravascular stents of various designs are currently in use to restore patency in atherosclerotic coronary arteries and it has been found that different stents have different in-stent restenosis rates. It has been hypothesized that the level of vascular injury caused to a vessel by a stent determines the level of restenosis. Computational studies may be used to investigate the mechanical behaviour of stents and to determine the biomechanical interaction between the stent and the artery in a stenting procedure. In this paper, we test the hypothesis that two different stent designs will provoke different levels of stress within an atherosclerotic artery and hence cause different levels of vascular injury. The stents analysed using the finite-element method were the S7 (Medtronic AVE) and the NIR (Boston Scientific) stent designs. An analysis of the arterial wall stresses in the stented arteries indicates that the modular S7 stent design causes lower stress to an atherosclerotic vessel with a localized stenotic lesion compared to the slotted tube NIR design. These results correlate with observed clinical restenosis rates, which have found higher restenosis rates in the NIR compared with the S7 stent design. Therefore, the testing methodology outlined here is proposed as a pre-clinical testing tool, which could be used to compare and contrast existing stent designs and to develop novel stent designs.     

Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution

In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modelled to investigate the drug release and spatio-temporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic–anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but with very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration.     

Murine Model of Femoral Artery Wire Injury with Implantation of a Perivascular Drug Delivery Patch

Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. While these therapies lead to the rapid restoration of blood flow, these technologies remain limited by restenosis in the case of bare metal stents and angioplasty, or reduced healing and possibly enhanced risk of thrombosis in the case of drug eluting stents. A key pathophysiological mechanism in the formation of restenosis is intimal hyperplasia caused by the activation of vascular smooth muscle cells and inflammation due to arterial stretch and injury. Surgeries that induce arterial injury in genetically modified mice are useful for the mechanistic study of the vascular response to injury but are often technically challenging to perform in mouse models due to the their small size and lack of appropriate sized devices. We describe two approaches for a surgical technique that induces endothelial denudation and arterial stretch in the femoral artery of mice to produce robust neointimal hyperplasia. The first approach creates an arteriotomy in the muscular branch of the femoral artery to obtain vascular access. Following wire injury this arterial branch is ligated to close the arteriotomy. A second approach creates an arteriotomy in the main femoral artery that is later closed through localized cautery. This method allows for vascular access through a larger vessel and, consequently, provides a less technically demanding procedure that can be used in smaller mice. Following either method of arterial injury, a degradable drug delivery patch can be placed over or around the injured artery to deliver therapeutic agents.