Local Vascular Delivery Research Articles

Abstract 300: A Biodegradable Wrap for Peri-vascular Delivery of Pro-resolving Lipid Mediators

Introduction: Persistent inflammation following vascular injury leads to excessive scarring, limiting the success of vascular interventions. Recent work has identified that endogenous specialized proresolving lipid mediators (SPM) such as resolvin D1 (RvD1) actively orchestrate the process of resolution, exerting vasculo-protective effects without associated toxicity. We propose local vascular delivery of SPM through a biodegradable wrap. Methods: RvD1 (200 ng) was heat-sealed between thin layers of polycaprolactone (PCL) or poly-lactic-co-glycolic acid (PLGA). PLGA membranes differed in their composition of lactic versus glycolic acid (%-lactide). Directional drug release was measured via EIA in a cell-free system in vitro and into rabbit aortas exposed to pulsatile flow ex vivo. Bioactivity was confirmed on human vascular smooth muscle cells (VSMC) using migration and proliferation assays. Results: Of the constructs tested, a 3-layered PLGA wrap consisting of 85%/75%/50%-lactide provided the most favorable drug elution (Fig1a), with sustained release of >800 pg/day for at least 14 days and nearly all elution occurring from the 50%-lactide side (Fig1b). Perivascular application of this wrap ex vivo with the 50%-lactide side facing “in” demonstrated uptake into rabbit aortic walls at 8 hours (0.4 ± 0.1 pg/mg). VSMC cultures exposed to drug-loaded wraps showed inhibition of migration (40%) and proliferation (25%). Conclusion: We demonstrate sustained and directional elution of therapeutically relevant amounts of biologically-active RvD1 through a biodegradable perivascular wrap, providing opportunity for translational studies of SPM in vascular injury.

PEGylated estradiol benzoate liposomes as a potential local vascular delivery system for treatment of restenosis

This study was directed towards the preparation and optimization of PEGylated (PEG, poly(ethylene glycol)) estradiol benzoate (ESB)-loaded liposomes to be used for the treatment of restenosis by local vascular delivery. Various liposomal formulations were prepared by thin film hydration method followed by sonication. Response surface methodology was applied to study the influence of three different independent variables, on the response of entrapment efficiency (%EE). Liposomes were characterized in terms of size, zeta potential, %EE and release profile. Incorporation of ESB was higher in egg phosphatidylcholine (EPC) liposomes, whereas the drug was displaced from liposomes, as the cholesterol (Chol) content of liposome increased. The optimum formulation composed of EPC/dioleyloxy trimethylammonium propane/distearoylphosphatidylethanolamine-PEG2000 with a molar proportion of 8.5:1:0.5 had the highest EE. In vivo studies in the balloon-injured rat carotid arteries revealed the potential of ESB-loaded liposomes as efficient local and controlled drug delivery systems to reduce restenosis.

Use of remote film loading methodology to entrap sirolimus into liposomes: Preparation, characterization and in vivo efficacy for treatment of restenosis

The main objective of this study was to formulate an effective controlled-release liposomal drug delivery system for sirolimus (SIR), a potent antiproliferative and anti-inflammatory drug, to be used for the treatment of restenosis following local vascular delivery. Liposomes were prepared using remote film loading method and characterized with regard to entrapment efficiency (EE), size distribution and zeta potential. The effects of key formulation and proceeding variables on both EE and drug release were studied using a fractional factorial design. By means of this entrapment technique, 98% SIR incorporation was achieved. Nanoliposomes were found to have average size of 110 nm and zeta potential of −9 mV. Developed formulations were found to have prolonged drug release for up to 3 weeks in vitro; this was best fitted by the Higuchi model. Other scopes of this work were to determine the applicability of sirolimus-loaded nanoliposomes (SIR-L) as drug carriers for the treatment of restenosis and to evaluate the effect of the presence of rigid lipids on the in vivo efficacy of the liposomal carrier of SIR. In vivo studies in balloon injured rat carotid arteries revealed the potential of SIR-loaded liposomes as efficient local and controlled drug delivery systems to reduce restenosis.

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 μg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 ± 0.10 versus 0.48 ± 0.10 mm2, p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 ± 0.87 versus 1.62 ± 0.71 mm2, p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia. (Int J Cardiovasc Intervent 2003; 5: 166-171)

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model.

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 microg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 +/- 0.10 versus 0.48 +/- 0.10 mm(2), p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 +/- 0.87 versus 1.62 +/- 0.71 mm(2), p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia.

Heparin Infusion Prior to Stenting (HIPS) trial: Final results of a prospective, randomized, controlled trial evaluating the effects of local vascular delivery on intimal hyperplasia

Background Local delivery of pharmacologic agents or genes at the site of angioplasty is a promising approach to reduce restenosis. However, there are unresolved questions concerning the safety and feasibility of local vascular delivery in clinical practice as well as the efficacy of delivered drug. To this end, the safety, feasibility, and efficacy of local delivery of heparin were evaluated in the Heparin Infusion Prior to Stenting (HIPS) trial. Methods and Results A total of 179 patients were enrolled in this multicenter, randomized, prospective, core laboratory–evaluated trial. Patients were randomly assigned to 5000 U heparin either administered to the coronary artery lumen or infused into the arterial wall immediately after angioplasty and before stent placement. End points included procedural events and clinical, angiographic, and intravascular ultrasound events at 6 months. Patient groups were evenly matched. There was no difference in the incidence of arterial injury, defined as an increase in arterial dissection, acute closure, or decrease in Thrombolysis In Myocardial Infarction grade blood flow in the group receiving local delivery. At follow-up there was no difference in the major adverse event rate between intraluminal (22.7%) and local groups (24.7%). There was no difference between intraluminal and local therapy in the angiographic in-stent restenosis rate (12.5%, 12.7%) or the in-stent volumetric analysis by intravascular ultrasound (IVUS) (37.19 ± 20.86 mm3 vs 43.79 ± 25.52 mm3). Conclusions Local delivery of 5000 U heparin into the arterial wall before stent implantation is safe and feasible. There was not a favorable effect of locally delivered heparin on clinical, angiographic, or IVUS end points of restenosis. The use of IVUS to measure volume of intimal hyperplasia in a multicenter, core laboratory–controlled trial is feasible. (Am Heart J 2000;139:1061-70.)

Sustained Intramural Retention and Regional Redistribution Following Local Vascular Delivery of Polylactic-Coglycolic Acid and Liposomal Nanoparticulate Formulations Containing Probucol.

BACKGROUND: Probucol reduces restenosis after angioplasty, provided oral administration is begun 1 month before the procedure. Local vascular delivery of a nonoparticulate formulation of probucol may obviate the need for drug loading by acutely raising arterial intramural concentration while providing sustained intramural retention. To test this hypothesis, we compared the retention and redistribution of (35)S-probucol encapsulated in either liposomal or polylactic-coglycolic acid (PLGA) nanoparticles after local vascular delivery. METHODS: Nanoparticles were delivered using a Crescendo microporous infusion catheter (Cordis, Warren, NJ) after balloon angioplasty of rabbit iliac arteries (n = 12-18 arteries per formulation per time point). Animals were euthanized on day 0, 3, or 7 after delivery. Iliac arteries, perivascular fat, and downstream tissues were harvested and the radioactivity disintegrations per minute was measured. Autoradiographic and confocal microscopic analyses of tissue sections were performed to evaluate intramural distribution of probucol. RESULTS: Immediately after delivery, radioactivity in the iliac arteries (log[dpm/mg], mean +/- SEM) was greater with PLGA (2.72 +/- 0.08) than with liposomal encapsulation (2.10 +/- 0.08, P = 0.001). Intramural retention of probucol was 23% at 7 days using liposomes and 10% using PLGA, corresponding to a probucol concentration of 0.1 ng/mg tissue for both formulations. By the third day after delivery, radioactivity in peri-iliac fat, femoral arteries, and hindlimb muscle increased by 88%, 29%, and 154%, respectively. Thereafter, radioactivity decreased to 56%, 43%, and 134% of initial dpm respectively, by day 7. CONCLUSIONS: although delivery efficiency was superior with PLGA encapsulation, intramural probucol concentrations were similar on day 7 using both formulations. Radial and axial redistribution of probucol was observed, indicating that this technique can be exploited to increase adjacent tissue delivery.

Increased Intramural Retention After Local Delivery of Molecules with Increased Binding Properties: Implications for Regional Delivery of Pharmacologic Agents.

BACKGROUND: Catheter-based local vascular delivery results in concentrated qualtities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural retention. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. METHODS AND RESULTS: The delivery efficiency and intramural retention of 2 mL of saline containing I(125) labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60% +/- 0.42% for albumin, 1.98% +/- 0.88% for PDGF (P =.001), and 0.31% +/- 0.11% for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF (P =.0001 for PDGF). Infusate covering >50% of the medial area was observed in 85% of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantlylonger for bFGF (P <.001). CONCLUSIONS: Molecules that exhibit preferential intramural binding show a longer intramural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.