Locally delivered nanoencapsulate tyrphostin (AGL-2043) reduces neointima formation in balloon-injured rat carotid and stented porcine coronary arteries

Department of Biological Chemistry, Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel
Biomaterials (Impact Factor: 8.56). 03/2005; 26(4):451-61. DOI: 10.1016/j.biomaterials.2004.02.040
Source: PubMed


Local delivery of antiproliferative drugs encapsulated in biodegradable nanoparticles (NP) has shown promise as an experimental strategy for preventing restenosis development. A novel PDGFRbeta-specific tyrphostin, AGL-2043, was formulated in polylactide-based nanoparticles and was administered intraluminally to the wall of balloon-injured rat carotid and stented pig coronary arteries. The disposition and elimination kinetics within the vessel wall, as well as the antirestenotic potential of the novel drug and delivery system, were evaluated. The efficacy and the local drug elimination kinetics were affected by the size of the NP and the drug-carrier binding mode. Despite similar arterial drug levels 90 min after delivery in rats, small NP were more efficacious in comparison to large NP (90 and 160 nm, respectively). AGL-2043 selectively inhibited vascular SMC in a dose-dependent manner. The antiproliferative effect of nanoencapsulated tyrphostin was considerably higher than that of surface-adsorbed drug. In the pig model, intramural delivery of AGL-2043 resulted in reduced in-stent neointima formation in the coronary arteries over control despite similar degrees of wall injury. The results of this study suggest that locally delivered tyrphostin AGL-2043 formulated in biodegradable NP may be applicable for antirestenotic therapy independent of stent design or type of injury.

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    • "A variety of different drug classes have been employed for the prevention of SMC growth and proliferation. These drugs include SMC growth inhibition agents: cytarabine, doxorubicin, vincristine 31, dalteparin sodium, cyclosporine A, colchicines, etoposide 32, sirolimus (rapamycin) 33, paclitaxel 34, and ceramide 35; antiplatelet drugs: cilostazol, eptifibatide and tirofiba 36,37; potential anti-inflammatory agents: clodronate, pamidronate, alendronate, and ISA-13-1 38,39; PDGF receptor specific drugs: tyrphostin (AG-1295 and AGL-2043) 40,41; and others: estrogen 42, troglitazone 43, tranilast 44, valsartan 45, statins 46, heparin, hirudin 47; and the Fab fragment inhibitor abciximab 37. Six Limus family-related drugs are currently being studied in DESs, namely sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus. Sirolimus, everolimus, biolimus A9, and zotarolimus all bind to the FK binding protein 12 (FKBP12), which subsequently binds to the mammalian target of rapamycin (mTOR) and thereby blocks the cell cycle of SMCs, mainly at the transition from the G1 to the S phase. "
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    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.
    Preview · Article · Jan 2014 · Theranostics
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    • "For these reasons, nanoparticles may be used to target drugs or genes to the endothelium to achieve sustained therapeutic effects. Several studies have shown that various nanoparticle formulations can reduce TGF-β1-induced intimal thickening and restenosis in animal models [31], [32]. In our study, nanoparticle-mediated delivery of a TGF-β1 antisense-expressing construct down-regulated the expression of TGF-β1 mRNA and protein and significantly inhibited intimal hyperplasia in grafted veins, demonstrating the feasibility of this strategy to target TGF-β1-induced intimal thickening. "
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    ABSTRACT: Intimal hyperplasia is one of the most important causes of vascular graft failure. Numerous studies have correlated transforming growth factor-β1 (TGF-β1) with extracellular matrix (ECM) deposition, a hallmark of intimal thickening. In the present study, we performed immunohistochemistry, RT-PCR, and Western blot to examine the dynamic expression of TGF-β1, TGF-β1 receptor type I (TGF-β RI), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) during intimal hyperplasia in grafted veins of a rat model generated by grafting a portion of the right internal jugular vein to the ipisiliary carotid artery. Additionally, we determined whether nanoparticle-mediated delivery of a TGF-β1 antisense-expressing construct prevented TGF-β1 expression and intimal hyperplasia in grafted veins. In grafted veins, the expression of TGF-β1 significantly increased on day 3 after transplantation, peaked on day 7, slightly decreased on day 14, and returned to baseline levels on day 28. The positive expression of TGF-β RI in grafted veins remarkably increased on day 7, peaked on day 14, and decreased thereafter. MMP-1 expression decreased significantly, while TIMP-1 expression increased, significantly on days 14 and 28. Nanoparticle-mediated delivery of a TGF-β1 antisense-expressing construct down-regulated TGF-β1 expression and inhibited intimal hyperplasia in grafted veins. Our findings provide further evidence that TGF-β1 plays an integral role in the development of intimal hyperplasia after vascular injury. Nanoparticle-mediated delivery of a TGF-β1 antisense-expressing construct is a feasible strategy to target TGF-β1-induced intimal thickening.
    Preview · Article · Jul 2012 · PLoS ONE
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    • "PLA AG-1295 nanoparticles were delivered via an infusion catheter in a balloon injured swine model, resulting in inhibition of smooth muscle cell (SMC) growth. Further, another tyrphostin AGL-2043 encapsulated in in PLA nanoparticles inhibited restenosis in both balloon injured rat carotid artery and stented porcine artery models [24]. "
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    ABSTRACT: Coronary in stent restenosis remains a significant limitation to the long term efficacy of coronary artery stent placement. In this review the authors review the pathophysiology of coronary in stent restenosis, together with an overview of the current treatment modalities. The potential clinical utility of nanotechnology is also reviewed. The first human safety trial of systemic nanoparticle paclitaxel (nab-paclitaxel) for in stent restenosis (SNAPIST-I) is discussed. The results showed no significant adverse advents attributable to the nab-paclitaxel at 10 or 30 mg/m2, although moderate neutropenia, sensory neuropathy and mild to moderate reversible alopecia occurred at higher doses. No major adverse cardiac events were recorded at 2 months, whilst at 6 months, 4 target lesions required revascularisation. The investigators concluded therefore that systemic nab-paclitaxel was well tolerated at a dose of <70 mg/m2. To date however, no formal clinical evaluation has been reported as to the clinical utility of nab-paclitaxel, or any of the nano preparations discussed, for the suppression of coronary in stent restenosis.
    Full-text · Article · Apr 2011 · Vascular Cell
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