Sustained inhibition of intimal thickening. In vitro and in vivo effects of polymeric beta-cyclodextrin sulfate.

Abstract

Intimal thickening after vascular injury may be modulated in part by heparin binding growth factors. We hypothesized that placement of a therapeutic polymer in the periadventitial space capable of tightly binding growth factors might alter the vascular response to injury. We first demonstrated that incubation of rat aortic smooth muscle cells with an insoluble, sulfated polymer of fi-cyclodextrin (P-CDS) was associated with a dose-dependent inhibition of proliferation induced by fetal calf serum, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor BB, or epidermal growth factor. Preincubation studies of P-CDS with FGF-2 revealed a very rapid removal of mitogenic activity. Using radiolabeled FGF-2 (0.25 ,ug/ml), we observed a very rapid association rate (0.34±0.07 min-', n = 4) and a very slow dissociation rate (3.3±0.2 x 1iO min'-) at 370C, suggesting a high affinity interaction. Using both Transwell and linear under-agarose assays, we demonstrated a significant inhibition of random migration (chemokinesis) by P-CDS. Unsulfated polymeric B-cyclodextrin (P-CD) had little if any of these effects, suggesting that the high negative charge density of P-CDS was important for the effects. Finally, rats undergoing carotid artery balloon injury were randomized to treatment with periadventitial P-CDS or no treatment, and were killed at 4 (n = 20), 14 (n = 59), and 88 d (n = 14). Morphometric analysis demonstrated significant and sustained inhibition of intimal thickening in P-CDS-treated rats at 14 (P < 0.01) and 88 d (P < 0.05) using absolute intimal area or intima/media area ratios. No inhibition was seen in a group of rats treated with P-CD. In P-CDS-treated rats, bromodeoxyuridine labeling studies revealed fewer labeled smooth muscle cells in the intima at 14 d (P = 0.01), while staining with Evans blue revealed enhanced late endothelial cell regrowth. Thus, periadventitially applied sulfated I8-cyclodextrin polymer, which can tightly bind heparin binding growth factors, inhibits intimal thickening in vivo in a sustained fashion without using an additional delivery system. These studies suggest that cellular processes mediated by heparin binding growth factors may be modulated by P-CDS. (J. Clin. Invest. 1995Invest. .96:2583Invest. -2592

In vivo quantitative assessment of catheter patency in rats

“…It has been reported that heparin can inhibit smooth muscle cell proliferation after arterial injury (Lindner et al 1992, Volker et al 1995 and that intimal thickening after vascular injury may be modulated in part by heparin-binding growth factors (Bachinsky et al 1995). Our results show that for long-term catheter implantation via the external jugular vein, heparin alone in the lock solution cannot fully inhibit catheter fibrosis, and complete encapsulation of the catheter tip ensues within three weeks.…”

Cyclodextrin Drug Carrier Systems

“…In addition, the heparin-mimicking activity of cyclodextrin sulfates has been successfully applied to the inhibition of restenosis after the surgical approaches to the treatment of atherosclerosis, − the chromatographic separation of heparin binding proteins, , and the clinical diagnosis for direct determination of high-density and low-density lipoproteins in serum. , …”

“…In particular, the oral administration of the aluminum salt of β-cyclodextrin sulfate loaded with basic fibroblast growth factor had the most prominent healing effects on the ulcers. 326 In addition, the heparin-mimicking activity of cyclodextrin sulfates has been successfully applied to the inhibition of restenosis after the surgical approaches to the treatment of atherosclerosis, [328][329][330] the chromatographic separation of heparin binding proteins, 331,332 and the clinical diagnosis for direct determination of high-density and low-density lipoproteins in serum. 333,334…”

Pharmaceutical Applications of Cyclodextrins. III. Toxicological Issues and Safety Evaluation

“…The failure rate due to restenosis after these approaches is high (30-50%), and much of the restenosis may be due to further inflammation, smooth muscle accumulation, and thrombosis. 189 Other studies have shown that a potassium salt of tri[6-benzylthio-6-deoxy]--CD hexadecasulfate is an orally active inhibitor for the replication of human immunodeficiency retrovirus with low anticoagulant activity and acute toxicity. The potential of heparin is, however, limited by the inability to use high doses due to its anticoagulant effect and the need to use subcutaneous administration.…”