Liposomal Alendronate Inhibits Systemic Innate Immunity and Reduces In-Stent Neointimal Hyperplasia in Rabbits

Abstract

Background-Innate immunity is of major importance in vascular repair. The present study evaluated whether systemic and transient depletion of monocytes and macrophages with liposome-encapsulated bisphosphonates inhibits experimental in-stent neointimal formation. Methods and Results-Rabbits fed on a hypercholesterolemic diet underwent bilateral iliac artery balloon denudation and stent deployment. Liposomal alendronate (3 or 6 mg/kg) was given concurrently with stenting. Monocyte counts were reduced by Ͼ90% 24 to 48 hours after a single injection of liposomal alendronate, returning to basal levels at 6 days. This treatment significantly reduced intimal area at 28 days, from 3.88Ϯ0.93 to 2.08Ϯ0.58 and 2.16Ϯ0.62 mm 2 . Lumen area was increased from 2.87Ϯ0.44 to 3.57Ϯ0.65 and 3.45Ϯ0.58 mm 2 , and arterial stenosis was reduced from 58Ϯ11% to 37Ϯ8% and 38Ϯ7% in controls, rabbits treated with 3 mg/kg, and rabbits treated with 6 mg/kg, respectively (meanϮSD, nϭ8 rabbits/group, PϽ0.01 for all 3 parameters). No drug-related adverse effects were observed. Reduction in neointimal formation was associated with reduced arterial macrophage infiltration and proliferation at 6 days and with an equal reduction in intimal macrophage and smooth muscle cell content at 28 days after injury. Conversely, drug regimens ineffective in reducing monocyte levels did not inhibit neointimal formation. Conclusions-Systemic

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

“…The degree of neointimal thickening was denoted as a unitless ratio of N/M area ( Table 2). N/M measurements were taken from the site of greatest luminal narrowing per artery, as this is the standard of the field and the most clinically relevant (19,30).…”

Liposomal Simvastatin Attenuates Neointimal Hyperplasia in Rats

“…Macrophage content in atherectomy tissue and the activation status of blood monocytes correlate with an increased rate of restenosis in humans (57,58). Recently, we have shown that transient and partial depletion of circulating monocytes by particulate dosage forms such as polymeric NP and liposomes-laden BPs suppresses neointimal formation and reduces experimental restenosis (12)(13)(14)(15)(16). It is suggested that, similarly to liposomal BPs (14-16), the inhibition of stenosis was mediated via simvastatin liposomes accumulation in circulating monocytes and their inactivation.…”

“…It is suggested that, similarly to liposomal BPs (14-16), the inhibition of stenosis was mediated via simvastatin liposomes accumulation in circulating monocytes and their inactivation. The partial and transient depletion of circulating monocytes results in reduced number of macrophages at the injury site and consequently with a diminished inflammatory response (14)(15)(16).…”

“…A preferential uptake of intact 'conventional' liposomes containing serotonin by circulating monocytes has been demonstrated recently (44). We hypothesized that encapsulation of statins in a suitable liposomal formulation, similarly to liposomal BPs (14)(15)(16)42,(44)(45)(46), will divert the statins from their main target (hepatocytes) to circulating monocytes resulting in systemic inactivation of monocytes and consequently, attenuation of neointimal formation. To the best of our knowledge, there are no reports in the literature on targeting circulating monocytes by a liposomal delivery system of statins for preventing restenosis.…”

“…The bisphosphonates (BPs), bone-seeking drugs, and osteoclasts inhibitors deplete circulating monocytes and inhibit macrophages when administered in a particulated dosage form, which is avidly phagocytosed by these cells. Recently, we have shown that partial and transient systemic inactivation of monocytes by polymeric nanoparticles (NP) and liposome-encapsulated BPs suppresses neointimal formation and reduces experimental restenosis (12)(13)(14)(15)(16).…”