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Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries.

ABSTRACT: Local drug delivery from polymer-coated stents has demonstrated efficacy for preventing in-stent restenosis; however, both the inflammatory effects of polymer coatings and concerns about late outcomes of drug-eluting stent use indicate the need to investigate innovative approaches, such as combining localized gene therapy with stent angioplasty. Thus, we investigated the hypothesis that adenoviral vectors (Ad) could be delivered from the bare-metal surfaces of stents with a synthetic complex for reversible vector binding.We synthesized the 3 components of a gene vector binding complex: (1) A polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethyleneimine (PEI) with pyridyldithio groups for amplification of attachment sites [PEI(PDT)], and (3) a bifunctional (amine- and thiol-reactive) cross-linker with a labile ester bond (HL). HL-modified Ad attached to PABT/PEI(PDT)-treated steel surfaces demonstrated both sustained release in vitro over 30 days and localized green fluorescent protein expression in rat arterial smooth muscle cell cultures, which were not sensitive to either inhibition by neutralizing anti-Ad antibodies or inactivation after storage at 37 degrees C. In rat carotid studies, deployment of steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated both site-specific arterial Ad(GFP) expression and adenovirus-luciferase transgene activity per optical imaging. Rat carotid stent delivery of adenovirus encoding inducible nitric oxide synthase resulted in significant inhibition of restenosis.Reversible immobilization of adenovirus vectors on the bare-metal surfaces of endovascular stents via a synthetic complex represents an efficient, tunable method for sustained release of gene vectors to the vasculature.

SUBMITTER: Fishbein I

PROVIDER: S-EPMC3384493 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries.

Fishbein Ilia I Alferiev Ivan I Bakay Marina M Stachelek Stanley J SJ Sobolewski Peter P Lai Meizan M Choi Hoon H Chen I-W IW Levy Robert J RJ

Circulation 20080414 16

<h4>Background</h4>Local drug delivery from polymer-coated stents has demonstrated efficacy for preventing in-stent restenosis; however, both the inflammatory effects of polymer coatings and concerns about late outcomes of drug-eluting stent use indicate the need to investigate innovative approaches, such as combining localized gene therapy with stent angioplasty. Thus, we investigated the hypothesis that adenoviral vectors (Ad) could be delivered from the bare-metal surfaces of stents with a sy ...[more]

PMID: 18413497

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Project description:ObjectivesTo assess patients' perspective about factors associated with stent choice.BackgroundDrug eluting stents (DES) markedly reduce the risk of repeat percutaneous coronary intervention (PCI), but necessitate a longer duration of dual anti-platelet therapy (DAPT) as compared with bare metal stents (BMS). Thus, understanding patients' perspective about factors associated with stent choice is paramount.MethodsPatients undergoing angiography rated, on a 10-point scale, the importance (1 = not important, 10 = most important) of avoiding repeat revascularization and avoiding the following potential DAPT drawbacks: bleeding/bruising, more pills/day, medication costs and delaying elective surgery. The factor, or group of factors, that was rated highest by each patient was identified.ResultsAmong 311 patients, repeat revascularization was the single most important consideration to 14.4% of patients, while 20.6% considered avoiding one of the DAPT drawbacks as most important. Most patients (65%) considered avoiding at least one DAPT drawback as important as avoiding repeat revascularization. In no subgroup of patients did more than a quarter of patients prefer avoiding repeat revascularization above all other concerns. Among patients undergoing PCI, more than three quarters received a DES, regardless of their stated preferences (DES use among those most valuing DES benefits, avoiding DAPT drawbacks, or both equally were 78.7%, 86.2%, and 85.6%, respectively, P = 0.56).ConclusionMost patients reported that avoiding DAPT drawbacks was as important as avoiding repeat revascularization. Eliciting patient preferences regarding stent type can enhance shared decision-making and allow physicians to better tailor stent choice to patients' goals and values.Trial registrationDeveloping and Testing a Personalized Evidence-based Shared Decision-making Tool for Stent Selection (DECIDE-PCI). ClinicalTrials.gov Identifier: NCT02046902. URL: https://clinicaltrials.gov/ct2/show/NCT02046902 © 2017 Wiley Periodicals, Inc.

Project description:Given the limited salvage options for in-stent restenosis (ISR) of drug-eluting stents (DES), our high-volume cardiac catheterization laboratory has been performing intracoronary brachytherapy (ICBT) in patients with recurrent ISR of DES. This study analyzes their baseline characteristics and assesses the safety/toxicity of ICBT in this high-risk population.A retrospective analysis of patients treated with ICBT between September 2012 and December 2014 was performed. Patients with ISR twice in a single location were eligible. Procedural complications included vessel dissection, perforation, tamponade, slow/absent blood flow, and vessel closure. Postprocedural events included myocardial infarction, coronary artery bypass graft, congestive heart failure, stroke, bleeding, thrombosis, embolism, dissection, dialysis, or death occurring within 72 hours. A control group of patients with 2 episodes of ISR at 1 location who underwent percutaneous coronary intervention without ICBT was identified. Unpaired t tests and χ2 tests were used to compare the groups.There were 134 (78%) patients in the ICBT group with 141 treated lesions and 37 (22%) patients in the control group. There was a high prevalence of hyperlipidemia (>95%), hypertension (>95%), and diabetes (>50%) in both groups. The groups were well-balanced with respect to age, sex, and pre-existing medical conditions, with the exception of previous coronary artery bypass graft being more common the ICBT group. Procedural complication rates were low in the control and ICBT groups (0% vs 4.5%, P = .190). Postprocedural event rates were low (<5%) in both groups. Readmission rate at 30 days was 3.7% in the ICBT group and 5.4% in the control group (P = .649).This is the largest recent known series looking at ICBT for recurrent ISR of DES. ICBT is a safe treatment option with similarly low rates (<5%) of procedural and postprocedural complications compared with percutaneous coronary intervention alone. This study establishes the safety of ICBT in a high-risk patient cohort.

Project description:ObjectiveTo compare the efficacy and safety of biodegradable polymer drug eluting stents with those of bare metal stents and durable polymer drug eluting stents.DesignMixed treatment comparison meta-analysis of 258,544 patient years of follow-up from randomized trials.Data sources and study selectionPubMed, Embase, and Central were searched for randomized trials comparing any of the Food and Drug Administration approved durable polymer drug eluting stents (sirolimus eluting, paclitaxel eluting, cobalt chromium everolimus eluting, platinum chromium everolimus eluting, zotarolimus eluting-Endeavor, and zotarolimus eluting-Resolute) or biodegradable polymer drug eluting stents, with each other or against bare metal stents.OutcomesLong term efficacy (target vessel revascularization, target lesion revascularization) and safety (death, myocardial infarction, stent thrombosis). Landmark analysis at more than one year was evaluated to assess the potential late benefit of biodegradable polymer drug eluting stents.ResultsFrom 126 randomized trials and 258,544 patient years of follow-up, for long term efficacy (target vessel revascularization), biodegradable polymer drug eluting stents were superior to paclitaxel eluting stents (rate ratio 0.66, 95% credibility interval 0.57 to 0.78) and zotarolimus eluting stent-Endeavor (0.69, 0.56 to 0.84) but not to newer generation durable polymer drug eluting stents (for example: 1.03, 0.89 to 1.21 versus cobalt chromium everolimus eluting stents). Similarly, biodegradable polymer drug eluting stents were superior to paclitaxel eluting stents (rate ratio 0.61, 0.37 to 0.89) but inferior to cobalt chromium everolimus eluting stents (2.04, 1.27 to 3.35) for long term safety (definite stent thrombosis). In the landmark analysis after one year, biodegradable polymer drug eluting stents were superior to sirolimus eluting stents for definite stent thrombosis (rate ratio 0.29, 0.10 to 0.82) but were associated with increased mortality compared with cobalt chromium everolimus eluting stents (1.52, 1.02 to 2.22). Overall, among all stent types, the newer generation durable polymer drug eluting stents (zotarolimus eluting stent-Resolute, cobalt chromium everolimus eluting stents, and platinum chromium everolimus eluting stents) were the most efficacious (lowest target vessel revascularization rate) stents, and cobalt chromium everolimus eluting stents were the safest with significant reductions in definite stent thrombosis (rate ratio 0.35, 0.21 to 0.53), myocardial infarction (0.65, 0.55 to 0.75), and death (0.72, 0.58 to 0.90) compared with bare metal stents.ConclusionsBiodegradable polymer drug eluting stents are superior to first generation durable polymer drug eluting stents but not to newer generation durable polymer stents in reducing target vessel revascularization. Newer generation durable polymer stents, and especially cobalt chromium everolimus eluting stents, have the best combination of efficacy and safety. The utility of biodegradable polymer stents in the context of excellent clinical outcomes with newer generation durable polymer stents needs to be proven.

Dataset Information

Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries.

Publications

Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries.

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