Drugs can be incorporated into nanoparticle loaded microbubbles and thus be delivered to magnetizable stents from circulating fluids by applying external magnetic fields. This technology could allow for post-hoc drug coating of already implanted vascular stents.
Acharya et al. 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. 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 the PCL matrix had the lowest platelet adhesion rate.
Subsequently, stents coated with the PCL matrix were subjected to further optimization processes for the improvement of surface morphology and the enhancement of the drug release duration. The results of the study demonstrated that a PCL matrix containing GSNO is a promising system for stent surface coating against restenosis. The main preclinical studies of nanoparticle DESs for the prevention and treatment of coronary restenosis are summarized in Table 1.
Gene-eluting stents GESs employ the use of stents as permanent scaffolds to achieve localized and sustained delivery of therapeutic genes to the affected vessel wall [ ].
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Utilizing nanotechnology, sustained and localized delivery of genes can mitigate problems of restenosis and late stent thrombosis by accelerating the regenerative capacity of re-endothelialization. Initial studies in the field of vascular gene therapy explored the use of catheters, such as the double balloon, single lumen porous balloon, Dispatch coil balloon, and Infiltrator nipple balloon catheters, to deliver both viral and non-viral gene vectors. Although these approaches were able to achieve localized delivery of therapeutic genes in conjunction with the balloon angioplasty procedure [ , ], several major limitations prolonged total occlusion of the target vessel; damage to the vessel wall and the induction of inflammatory responses and neointimal hyperplasia; and low levels of gene transfer efficiency have dampened further advancement in the field.
In recent years, there has been a surge of interest in and preference for balloon-expandable GESs over catheters as a platform for gene delivery. GESs represent a more appealing method for gene delivery to atherosclerotic coronary vessels for the following reasons: first, vector immobilization to stent struts allows for increased local concentration of the therapeutic drug at the targeted arterial segment without distal spread to nontarget tissue, thereby avoiding systemic toxicity and increasing the chance of effective gene transfection to adjacent cells [ , , ].
Second, the therapeutic effect is targeted to the anticipated site of pathophysiological processes such as mural thrombosis and vascular SMC proliferation [ ]. Third, there is already extensive clinical experience in coronary stenting procedures, making it extremely convenient to combine revascularization with gene delivery in a single procedure [ ].
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Fourth, stents are able to act as permanent scaffolding structures and reservoirs for prolonged vector release. Finally, stent-tethered vectors can better persist in tissues as they are physically protected from the shearing effect of blood flow [ ]. Although there are several major limitations, a significant amount of work has been accomplished in the field of non-viral nanoparticle-based gene delivery.
Numerous transgenes have been shown to be effective in reducing restenosis in animal models, and various modes of local gene delivery have been developed. There are four main molecular targets that researchers have focused on: reduction of neointimal hyperplasia; acceleration of re-endothelialization; inhibition of thrombosis; and reduction of inflammation.
Of these targets, the inhibition of restenosis via a reduction in neointimal hyperplasia has been the most studied method. Gene therapy is an appealing way to prevent restenosis by delivering therapeutic genes into the vascular tissue. Many previous studies utilized either intravenous injection or balloon catheters to introduce genes and carriers to blood vessel. Unlike other gene therapies, cardiovascular gene therapy encounters the obstacle of specifically delivering therapeutic genes to the target site, not the blood circulatory system.
The use of endovascular stents as scaffolds for the localized and prolonged delivery of therapeutic genes into the diseased blood vessel wall would provide a promising solution for gene therapy of ISR [ , ]. However, endovascular stent as a percutaneous gene delivery device needs to be improved upon mainly due to insufficient gene loading. Non-viral gene delivery has been considered safer than its viral counterpart. Strategies for enhancing non-viral gene delivery typically involve the complexation of plasmids with cationic polymers or lipids, which can self-assemble with DNA to form particles capable of being endocytosed by cells.
Substrate-mediated delivery results in the immobilization of DNA complexed with the carrier onto the substrate. Immobilization on the target surface can enhance gene transfer by maintaining an elevated concentration of DNA within the cellular microenvironment via sustained release and by facilitating subsequent cellular internalization [ ].
The modulation of genes with plasmid DNA and RNA interference has been used to modulate the local concentrations of specific signaling molecules that inhibit the growth of certain cells while promoting the growth of others.
The key point for each of these therapies is to inhibit the growth of vascular SMCs while promoting re-endothelialization of the vessel, so as to reverse the injured vessel back into a healthy vessel. A variety of different gene targets have been used to treat restenosis. Restenosis gene therapies can be categorized by their method of action and their cellular target [ ], e.
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A large array of gene delivery vectors has been evaluated for their ability to introduce therapeutic genes into vascular tissue. Vectors for gene delivery can be broadly classified into 2 categories: viral and non-viral vectors. Klugherz et al. The plasmid DNA was effectively delivered to only the stented site within 24 h of stent implantation, with no evidence of systemic expression. Transgene expression was detectable in the stented site up to 10 days after implantation, which was sufficient to exert a therapeutic effect.
Cationic lipid-mediated iNOS gene transfer combined with local delivery by an Infiltrator infusion catheter was shown to enable sufficiently high expression of iNOS protein to bring about therapeutic efficacy in diminishing neointimal formation. Using a similar liposomal system, Brito et al. The results of a recent study by Sharif et al. In addition, viral-mimicking liposomes [such as the hemagglutinating virus of Japan HVJ -liposome] have also been investigated as gene vectors, and have been established to be highly reliable and superior to conventional liposomal carriers [ , , , , , , ].
Polymeric nanoparticle-based gene delivery: In contrast to lipid nanoparticle-based delivery, few studies have explored polymeric nanoparticle-based vectors for intravascular gene delivery. An in vitro study by Kim et al. Another novel polymeric nanoparticle-based gene delivery approach was described by Zhu et al.
PLGA nanoparticles encapsulating ODNs have been previously shown to enhance cellular uptake via endocytosis, increase resistance to nuclease degradation, offer sustained release of ODNs, and subsequently prolong the duration of ODN antisense action. Indeed, the study by Cohen-Sacks et al. Unlike non-viral vectors, fewer studies have investigated adenoviral vector tethering on nanoparticle surfaces [ , , - ].
An antiadenoviral antibody tethering method was employed to bind adenoviral vectors to a collagen-coated stent to allow controlled, site-specific, localized release and improve transduction efficacy. Later studies followed suit, using a variety of methods to tether adenoviral vectors to the stent surface through highly specific affinity immobilization [ , , ]. A study by Levy's group in [ ] explored the possibility of using an entirely synthetic strategy to tether adenoviral vectors to BMSs, which involved the use of a bifunctional cross-linking agent HL to bind both the adenoviral vector and a surface-modified stent.
Capsid proteins of adenovirus vectors were first covalently modified with the bifunctional HL and then tethered to the stent. Interestingly, an earlier study by the same group demonstrated that nanoparticle-adenovirus NP-Ad complexes formed from surface-activated polylactide PLA nanoparticles covalently attached to adenovirus-binding proteins achieved significantly higher levels of gene delivery and transgene expression than that did comparable amounts of free adenoviral vectors [ ].
Unfortunately, to date, there has not been a follow-up in vivo study on a local delivery strategy to deliver these nanoparticle-adenovirus complexes to the vasculature. Taken together, these studies provide strong evidence of the potential for nanotechology-based approaches to enhance existing viral and non-viral gene delivery methods. In most studies, the gene delivery platform is a polymer stent coating, which plays a crucial role in ensuring a compatible relationship between the BMS surfaces, the vessel wall, and circulating blood [ 13 , , , , , , , , , ].
Other studies, however, have explored the option of direct vector-tethering to BMS surfaces without the use of a polymer coating to prevent potential polymer-induced vascular injury and inflammatory responses [ , , ]. In recent years, nanotechnology has been employed in the design of stent-based gene delivery platforms, be it in nanotextured surfaces to enhance biocompatibility and improve cell-stent interactions [ , ] or in specifically targeted, nanoscale surface topographic modifications to improve interactions with blood and enhance endothelial attachment, proliferation, and migration [ ].
Polymers investigated include both synthetic [e. In most of these studies, the gene-encoding vector was attached to the stent surface by dip- or spray-coating the stent with vector-containing polymer that isa derivative of collagen. An alternative biocompatible stent coating recently investigated by Kim et al.
HA, a major glycosaminoglycan component of the extracellular matrix, has been shown to reduce thrombus formation when coated onto endovascular devices.
Despite the encouraging results obtained with the bulk immobilization of gene vectors on polymer stent coatings, several studies have opted instead for a vector-tethering strategy to exclude the need for a polymer coating [ , , , ]. Fishbein et al.
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Notably, Fishbein et al. This finding demonstrated that affinity-mediated vector-tethering allows for dense packing of the vector onto the stent surface. Antisense oligomers are polymers designed to interfere with the information transfer from the gene to the protein. Thus, they may target specific genetic sequences that potentially play an important role at particular stages of disease progression. AVI is a phosphorodiamidate morpholino oligomer, meaning that it is capable of binding to RNA in a sequence-specific fashion with sufficient avidity to be useful for the inhibition of the translation of the mRNA into protein in vivo, a result referred to as an 'antisense' effect.
The AVI antisense oligomer blocks the expression of the c-myc protein, which is responsible for many of the pathologic processes associated with restenosis. In the experimental setting, animal studies have shown that AVI can efficiently reduce neointimal formation without inducing aneurysm formation [ ].
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Forty-four patients with either de novo lesions or restenosis were randomized into low dose 3 mg , high dose 10 mg , and control groups. There was no in-hospital or day MACE recorded in any group. Clinical follow-up was available for 25 patients. These preliminary findings from this small cohort of patients require confirmation in a larger trial utilizing more sophisticated drug-eluting technologies.