Paclitaxel Inhibits Arterial Smooth Muscle Cell Proliferation and Migration In Vitro and In Vivo Using Local Drug Delivery

Axel, Dorothea I.; Kunert, W; Göggelmann, Christoph; Oberhoff, Martin; Herdeg, Christian; Küttner, A.; Wild, Doris H.; Brehm, Bernhard R.; Riessen, Reimer; Köveker, G.; Karsch, Karl R.

doi:10.1161/01.cir.96.2.636

Cited by 689 publications

(489 citation statements)

References 47 publications

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“…The degree of neointimal thickening was denoted as a unitless ratio of N/M area ( Table 2). N/M measurements were taken from the site of greatest luminal narrowing per artery, as this is the standard of the field and the most clinically relevant (19,30).…”

Section: Resultsmentioning

confidence: 99%

“…Because the animals were also given a repeat dose on day 5, increased collagen deposition may contribute to the antistenotic efficacy observed here. Effective repeat dosing that corresponds to lesion severity may be useful for chronic diseases like atherosclerosis (19,29), which may not always be resolved by revascularization alone (20).…”

Section: Discussionmentioning

confidence: 99%

“…Temporal control of drug delivery may facilitate endothelial healing after injury, as NPs may be used to deliver antiproliferative agents to the vascular wall when neointimal proliferation is most active, followed by complete degradation and clearance (18). Targeted NPs that bind to exposed antigens in injured arteries may help to achieve therapeutic doses at sites of injury, because antiproliferative drugs such as paclitaxel have to be localized for action (19). In particular, systemic delivery of antiproliferative drugs to the specific site of disease remains an attractive goal, given the ease of drug administration (20).…”

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confidence: 99%

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In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Chan

Rhee

Drum

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

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Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD. P ercutaneous coronary interventions (PCIs) using drug-eluting stents (DESs) are credited with significant reductions in vessel restenosis, due to the effective combination of a drug delivery system and mechanical scaffold (1). Despite the extensive clinical use of DESs to maintain vascular patency, not all coronary lesions are amenable to DES placement (2). In addition, DESs are associated with delayed endothelialization (3) and increased thrombogenicity (4, 5) that require extended antiplatelet treatment (6). In some cases, only bare metal stents (BMSs) may be applied, which lack the benefit of antirestenotic therapy and instead stimulate neointimal smooth muscle cell (SMC) proliferation (7,8).Nanomedicines may offer improvements to existing clinical treatments, including those for cardiovascular disorders (9, 10). Sub-100-nm organic nanoparticles (NPs) combine useful features of ultrasmall size (11, 12), surface modification (13), controlled drug release, biodegradability, and biocompatibility (14). Liposomal, polymeric, and albumin-based NPs have been formulated to improve drug solubility and deliver paclitaxel at doses higher than otherwise possible in circulation (15-17). Temporal control of drug delivery may facilitate endothelial healing after injury, as NPs may be used to deliver antiproliferative agents to the vascular wall when neointimal proliferation is most active, followed by complete degradation and clearance (18). Targeted NPs that bind to exposed antigens in injured arteries may help to achieve therapeutic doses at sites of injury, b...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Chan

Rhee

Drum

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

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“…PT also affects immune responses, expression of cytokines, and multiple other cellular functions [13,14,[27][28][29][30]. In addition, PT suppresses the migration and proliferation of tumor cell lines [23], epithelial cells [22], fibroblasts [24], and vascular smooth muscle cells [31]. The lipophilic PT molecule is rapidly taken up by cells [32], and has a long duration of action, even after a single dose applied topically [29,33].…”

Section: Discussionmentioning

confidence: 99%

“…The lipophilic PT molecule is rapidly taken up by cells [32], and has a long duration of action, even after a single dose applied topically [29,33]. Its effectiveness after local treatment has been demonstrated by inhibition of proliferation and migration of vascular smooth muscle cell in vitro and in vivo [31,34], and suppression of epithelial proliferation in a rat model of PC [12]. The inhibitory effects of PT on fibrogenesis in the biliary system raise the prospect that stents eluting this compound might be an effective means to prevent recurrent biliary strictures, a concept that has recently been demonstrated in a porcine model [35].…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel Interrupts TGF-β1 Signaling Between Gallbladder Epithelial Cells and Myofibroblasts

Choi

Savard

Choi

et al. 2007

Journal of Surgical Research

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Background-The cellular and molecular mechanisms of fibrogenesis in the extrahepatic biliary epithelium are not known. TGF-β1 is a cytokine implicated in signaling pathways that mediate collagen formation. An observation that paclitaxel (PT), applied topically into the rat common bile duct, inhibited stricture formation led us to hypothesize that PT's effects might be due to interruption of TGF-β1 signaling between biliary epithelial cells and subepithelial myofibroblasts.

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Coronary Artery Stents

Suwaidi¹

2000

JAMA

186

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Paclitaxel Inhibits Arterial Smooth Muscle Cell Proliferation and Migration In Vitro and In Vivo Using Local Drug Delivery

Cited by 689 publications

References 47 publications

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Paclitaxel Interrupts TGF-β1 Signaling Between Gallbladder Epithelial Cells and Myofibroblasts

Coronary Artery Stents

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