Nanoparticle drug- and gene-eluting stents for the prevention and treatment of coronary restenosis

Abstract

Percutaneous coronary intervention (PCI) has become the most common revascularization procedure for coronary artery disease. The use of stents has reduced the rate of restenosis by preventing elastic recoil and negative remodeling. However, in-stent restenosis remains one of the major drawbacks of this procedure. Drug-eluting stents (DESs) have proven to be effective in reducing the risk of late restenosis, but the use of currently marketed DESs presents safety concerns, including the non-specificity of therapeutics, incomplete endothelialization leading to late thrombosis, the need for long-term anti-platelet agents, and local hypersensitivity to polymer delivery matrices. In addition, the current DESs lack the capacity for adjustment of the drug dose and release kinetics appropriate to the disease status of the treated vessel. The development of efficacious therapeutic strategies to prevent and inhibit restenosis after PCI is critical for the treatment of coronary artery disease. The administration of drugs using biodegradable polymer nanoparticles as carriers has generated immense interest due to their excellent biocompatibility and ability to facilitate prolonged drug release. Despite the potential benefits of nanoparticles as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of nanoparticle materials, as well as to their size and shape. This review describes the molecular mechanism of coronary restenosis, the use of DESs, and progress in nanoparticle drug- or gene-eluting stents for the prevention and treatment of coronary restenosis.

Keywords: Coronary artery disease; Nanoparticle.; Restenosis; Stenosis; Stents.

Figure 1

Coronary atherosclerosis and coronary stenosis.

Figure 2

Percutaneous transluminal coronary angioplasty and coronary restenosis.

Figure 3

Stenting and coronary in-stent restenosis.

Figure 4

Rabbit restenotic model developed by balloon-injured abdominal aorta and high cholesterol diet. (A), normal abdominal aorta (Hematoxylin staining × 100); (B), restenotic abdominal aorta. The intima and media were significantly thickened (Immunohistochemical staining for proliferating cell nuclear antigen × 100); and (C), restenotic abdominal aorta. Proliferating cell nuclear antigen-positive cells and various inflammatory cells were found in the thickened intima (Immunohistochemical staining for proliferating cell nuclear antigen × 100).

Figure 5

Mechanisms of action of six Limus family-related drugs (sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus) and paclitaxel. (A), sirolimus, everolimus, biolimus A9, or zotarolimus forms a complex with the cytoplasmic protein FKBP12. The complex inhibits the growth factor-stimulated phosphorylation of two proteins, the p70 s6 kinase and 4E-BP1. The phosphorylation of those two proteins is controlled by the mammalian target of rapamycin (mTOR). (B), tacrolimus or pimecrolimus binds to FKBP506, forming a complex, which binds to and blocks calcineurin. The complex inhibits the activation of nuclear factor of activated T cells (NFAT), thus preventing its entrance into the nucleus and inhibiting T-cell activation. (C), paclitaxel is a microtubule inhibitor. It binds to β-tubulin proteins in the mitotic spindle, rendering them non-functional and thereby inhibits cell division in the G0/G1 and G2/M phases. PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; FKBP, FK binding protein; G0, G0 phase (resting phase); G1, G1 phase (cell enlarges and makes new protein); G2, G2 phase (preparation for division); M, M phase (cell division or mitosis); S, S phase (DNA replication).

Figure 6

Several common delivery systems for the treatment of coronary restenosis

Figure 7

Schematic diagrams of material design and function hypothesis. (A), the structure of bi-layered VEGF/PTX NPs and procedures of stent coating. The bare metal stents were pre-treated with laser beam which generates nano pores to increase the coating amount and stability. (B), assumed sequential release of VEGF/PTX and the mechanism of their function. The sequential releasing pattern allows rapid re-endothelialization in the early days and later inhibition of smooth muscle cell proliferation. Reproduced with permission from Elsevier Ltd.

Figure 8

Representative images of H & E staining of cross-sections 28 days after implantation. (A), bare stent; (B), blank NPs coated stent; (C), PTX NPs coated stent; (D), TAXUS^® stent; (E), VEGF NPs coated stent; (F), VEGF/PTX NPs coated stent. (× 40). Reproduced with permission from Elsevier Ltd.