The long term goal of this proposal is to improve the biocompatibility of metallic coronary stents by creating a hybrid device consisting of a removable metallic stent combined with an inert, nontoxic polymer capable of altering the genetic program of vascular endothelial and smooth muscle cells by delivering bioactive substances. Recently, the use of metallic coronary stenting has been demonstrated to lower restenosis in man. However, problems with long-term biocompatibility, potential for thrombosis, and late restenosis in 25-30% of patients remain to be solved. Vascular endothelial and smooth muscle cells synthesize and secrete a host of factors that contribute to thrombosis and neointimal hyperplasia. One strategy for reducing restenosis is to inhibit local growth and prothrombotic factor action using antibodies. bioactive substances, antisense oligonucleotides, of direct in-vivo gene delivery. Transcatheter devices capable of site-specifically delivering high concentrations of candidate therapeutic substances remain to be developed. Implantable stents combined with an appropriate biocompatible polymer offer an attractive deliver platform. Our objectives are to develop such a hybrid system. For this propose molecules capable of regulating the genetic program of vascular cells have been selected as candidate therapeutic substances for stent delivery: i) retinoic acid, a lipophilic vitamin A derivative known to increase local fibrinolysis. ii) octreotide. a hydrophilic polypeptide somatostatin analog believed to inhibit neointimal formation plan blocking local insulin-like growth factor l (IGF-1) expression, and iii) antisense oligonucleotide targeted against lGF-1 and the proto-oncogene c-myb. The following four specific aims are proposed: 1. Develop and characterize polymers capable of being bonded to metallic stents and incorporating a wide range of bioactive substances. Methods are presented for enhancing polymer biocompatibility and for incorporating antisense oligonucleotides and the polypeptide somatostatin analog octreotide into lipophilic polymers. 2. Develop a selection process to test the in-vitro kinetics of incorporation and release of each candidate agent. Thus with the best performance characteristics will be selected for further in-vivo testing and characterization. Tissue kinetics, bioactivity, toxicity, and leakage to non-target sites will be evaluated. 3. To use the polymer coated hybrid stent to test the hypothesis whether local delivery of sufficiently high amounts of retinoic acid will increase local tissue plasminogen activator mRNA levels and reduce thrombosis in a crush injury flow reduction model. 4. To investigate the role of local IGF-1 and c-myb production on neointimal hyperplasia by using the device to deliver anti sense oligonucleotides.
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