Pathological Analysis of Local Delivery of Paclitaxel Via a Polymer-Coated Stent

Farb, Andrew; Heller, Phillip F.; Shroff, Sweta; Cheng, L.; Kolodgie, Frank D.; Carter, Andrew J.; Scott, Douglas; Froehlich, Jeffrey P.; Virmani, Renu

doi:10.1161/hc3001.092037

Cited by 368 publications

(248 citation statements)

References 23 publications

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“…A small one-year study and subsequent large clinical trial with sirolimus reported a dramatic reduction of restenosis. 7,8 Although preclinical animal studies with either of these agents have demonstrated efficacy at 28 days, long-term studies show inconsistent results [2][3][4]9 (and Andrew J. Carter, MD, Providence Heart Institute, Providence, Ore, unpublished data, 2002; Alan W. Heldman, MD, Johns Hopkins University, Baltimore, Md, unpublished data, 2002). In humans, healing of a bare stainless steel stent usually takes between 3 and 6 months, whereas in animals this response is usually complete by 28 days.…”

Section: Discussionmentioning

confidence: 99%

“…3 The stented iliac segments were harvested after perfusion fixation with 10% neutral-buffered formalin.…”

Section: Histological Processingmentioning

confidence: 99%

“…1 For the prevention of in-stent restenosis, PXL is thought best delivered locally on a drug-eluting stent to achieve therapeutic concentrations without the risk of systemic toxicity. This rationale has been successfully applied in 28-day animal studies of in-stent neointimal growth; however, there is incomplete healing [2][3][4] and, in some instances, a lack of sustained neointimal suppression. 3 Alternative commercial systemic formulations of PXL containing the nonionic surfacant Cremophor EL (polyoxyethylated castor oil) have been previously avoided as systemic therapy for restenosis because of the risk of hypersensitivity reactions (despite prophylaxis) and long infusion rates over a period of 3 to 24 hours.…”

mentioning

confidence: 99%

“…This rationale has been successfully applied in 28-day animal studies of in-stent neointimal growth; however, there is incomplete healing [2][3][4] and, in some instances, a lack of sustained neointimal suppression. 3 Alternative commercial systemic formulations of PXL containing the nonionic surfacant Cremophor EL (polyoxyethylated castor oil) have been previously avoided as systemic therapy for restenosis because of the risk of hypersensitivity reactions (despite prophylaxis) and long infusion rates over a period of 3 to 24 hours. 5 Recently, a novel cremophor-free albumin-stabilized nanoparticle formulation of PXL (nPXL) was developed for rapid parenteral delivery.…”

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confidence: 99%

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Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel

et al. 2002

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Background-Paclitaxel (PXL)-eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth. The present study tested the efficacy of a novel systemic delivery nanoparticle PXL for reducing in-stent restenosis. Methods and Results-A saline-reconstituted formulation of PXL stabilized by albumin nanoparticles (nPXL) was tested in 38 New Zealand White rabbits receiving bilateral iliac artery stents. Doses of nPXL (1.0 to 5.0 mg/kg) were administered as a 10-minute intra-arterial infusion; control animals received vehicle (0.9% normal saline). In a follow-up chronic experiment, nPXL 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeat nPXL dose at 28 days; these studies were terminated at 3 months. At 28 days, mean neointimal thickness was reduced (PՅ0.02) by doses of nPXL Ն2.5 mg/kg with evidence of delayed healing. The efficacy of a single dose of nPXL 5.0 mg/kg, however, was lost by 90 days. In contrast, a second repeat dose of nPXL 3.5 mg/kg given 28 days after stenting resulted in sustained suppression of neointimal thickness at 90 days (PՅ0.009 versus single dose nPXL 5.0 mg/kg and controls) with nearly complete neointimal healing. Conclusions-Although systemic nPXL reduces neointimal growth at 28 days, a single repeat dose was required for sustained neointimal suppression. Thus, this novel systemic formulation of PXL may allow adjustment of dose at the stent treatment site and prove to be a useful adjunct for the clinical prevention of in-stent restenosis.

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Section: Discussionmentioning

confidence: 99%

“…3 The stented iliac segments were harvested after perfusion fixation with 10% neutral-buffered formalin.…”

Section: Histological Processingmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel

et al. 2002

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“…Recently, studies using coated stents that release rapamycin and paclitaxel have reported substantial decreases in the extent of in-stent restenosis during animal studies [8][9][10] and the initial phases of clinical trials. 11,12 However, coated stents could also be used to deliver genetic material to the cells of the vessel wall by diffusion from the polymer coating.…”

Section: Introductionmentioning

confidence: 99%

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

Takahashi

Palmer-Opolski²,

Smith

et al. 2003

Gene Ther

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Metallic stents coated with a polyurethane emulsion containing plasmid DNA were implanted in rabbit iliac arteries to evaluate transgene delivery and expression in the vessel wall. The expression of the plasmid-encoded marker genes, b-galactosidase, luciferase and green fluorescence protein (GFP), were evaluated at 7 days after implantation. In all cases, plasmid transfer was confined to the vessel wall at the site of stent implantation, plasmid DNA was not observed in vessel segments immediately proximal or distal to the stent and dissemination of plasmid DNA to lung, liver or spleen was not observed. Expression of transgenes occurred only in vessel segments in contact with the stent and analysis of the GFP expression pattern revealed a high frequency of marker protein-positive cells occurring at or near the luminal surface. The extent of transgene expression was dependent upon the quantity of DNA loaded onto the stent and no signal was detected in vessel segments that received polymer-coated stents lacking plasmid DNA. Of significance, colocalization studies identified transgene expression not only in vascular smooth muscle cells but also in macrophages. Hence, polymer-coated stents provide a new capability for transgene delivery to immune cells that are believed to contribute to the development of in-stent restenosis.

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Restenosis: Etiologies and Prevention

Sangiorgi¹,

Holmes²,

Schwartz³

2002

Evidence‐based Cardiology

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Pathological Analysis of Local Delivery of Paclitaxel Via a Polymer-Coated Stent

Abstract: Background-Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis.

Cited by 368 publications

References 23 publications

Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel

Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

Restenosis: Etiologies and Prevention

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