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

• Published in: Biomaterials 2005-02, Vol.26 (4), p.451-461
• Main Authors: Banai, Shmuel, Chorny, Michael, Gertz, S.David, Fishbein, Ilia, Gao, Jianchuan, Perez, Louise, Lazarovichi, Galila, Gazit, Aviv, Levitzki, Alexander, Golomb, Gershon
• Format: Article
• Language: English
• Subjects: Angioplasty, Balloon, Coronary - adverse effects; Animals; Blood Vessel Prosthesis - adverse effects; Cell Proliferation - drug effects; Cells, Cultured; Coated Materials, Biocompatible - administration & dosage; Coated Materials, Biocompatible - chemistry; Coated Materials, Biocompatible - pharmacokinetics; Controlled drug release; Coronary Restenosis - pathology; Coronary Restenosis - prevention & control; Dose-Response Relationship, Drug; Drug delivery; Drug Delivery Systems - methods; Endothelial Cells - drug effects; Endothelial Cells - pathology; Graft Occlusion, Vascular - pathology; Graft Occlusion, Vascular - prevention & control; In-stent restenosis; Injections; Intimal hyperplasia; Local delivery; Male; Materials Testing; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - pathology; Nanoparticles; Nanotubes - chemistry; Neointima; Pharmaceutical Vehicles - administration & dosage; Pharmaceutical Vehicles - chemistry; Polyesters - chemistry; Polyesters - pharmacokinetics; Protein tyrosine kinase blocker; Rats; Restenosis; Smooth muscle cell; Stent; Stents - adverse effects; Swine; Treatment Outcome; Tyrphostin; Tyrphostins - administration & dosage; Tyrphostins - pharmacokinetics
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2004.02.040

Local delivery of antiproliferative drugs encapsulated in biodegradable nanoparticles (NP) has shown promise as an experimental strategy for preventing restenosis development. A novel PDGFR β-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.