Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis

Einat Cohen-Sela; Ohad Rosenzweig; Jianchuan Gao; Hila Epstein; Irith Gati; Reuven Reich; Haim D. Danenberg; Gershon Golomb

doi:10.1016/j.jconrel.2006.03.010

Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis

Einat Cohen-Sela, Ohad Rosenzweig, Jianchuan Gao, Hila Epstein, Irith Gati, Reuven Reich, Haim D. Danenberg, Gershon Golomb^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Systemic transient depletion of monocytes and macrophages by liposome-encapsulated bisphosphonates (BPs), reduces neointimal formation in experimental restenosis. The aim of this study was to examine the antirestenotic effect of a polymeric nanoparticulate formulation containing the BP alendronate (ALN). The BP was successfully formulated in polylactide-co-glycolide (PLGA) nanoparticles (NP). ALN NP with negative charge, size of 223 ± 64 nm, and high entrapment efficiency (55.1%) have been formulated. ALN NP exhibited a significant cytotoxic effect, in a dose-response relationship, on macrophage-like RAW264 cells in cell culture. Subcutaneously (SC) administrated ALN NP (1.5 mg/kg on days - 1 and + 6) resulted in a significant attenuation of neointima to media ratio (N/M) by 52.7% and stenosis by 39.7% 28 days after balloon injury in the hypercholesterolemic rabbit model. Moreover, a good correlation was found between macrophage abundance in the injured arteries and the extent of stenosis. ALN NP treatment resulted in the reduction of both interleukin-1β and matrix metalloproteinases (2 and 9). It is concluded that a particulated dosage form of polymeric NP loaded with ALN reduce neointimal formation in vivo by systemic transient depletion of monocytes.

Original language	English
Pages (from-to)	23-30
Number of pages	8
Journal	Journal of Controlled Release
Volume	113
Issue number	1
DOIs	https://doi.org/10.1016/j.jconrel.2006.03.010
State	Published - 12 Jun 2006

Keywords

Angioplasty
Anti-inflammatory
Bisphosphonates
Immunomodulation
Monocytes/macrophages
Nanoparticles
Restenosis

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10.1016/j.jconrel.2006.03.010

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title = "Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis",

abstract = "Systemic transient depletion of monocytes and macrophages by liposome-encapsulated bisphosphonates (BPs), reduces neointimal formation in experimental restenosis. The aim of this study was to examine the antirestenotic effect of a polymeric nanoparticulate formulation containing the BP alendronate (ALN). The BP was successfully formulated in polylactide-co-glycolide (PLGA) nanoparticles (NP). ALN NP with negative charge, size of 223 ± 64 nm, and high entrapment efficiency (55.1%) have been formulated. ALN NP exhibited a significant cytotoxic effect, in a dose-response relationship, on macrophage-like RAW264 cells in cell culture. Subcutaneously (SC) administrated ALN NP (1.5 mg/kg on days - 1 and + 6) resulted in a significant attenuation of neointima to media ratio (N/M) by 52.7% and stenosis by 39.7% 28 days after balloon injury in the hypercholesterolemic rabbit model. Moreover, a good correlation was found between macrophage abundance in the injured arteries and the extent of stenosis. ALN NP treatment resulted in the reduction of both interleukin-1β and matrix metalloproteinases (2 and 9). It is concluded that a particulated dosage form of polymeric NP loaded with ALN reduce neointimal formation in vivo by systemic transient depletion of monocytes.",

keywords = "Angioplasty, Anti-inflammatory, Bisphosphonates, Immunomodulation, Monocytes/macrophages, Nanoparticles, Restenosis",

author = "Einat Cohen-Sela and Ohad Rosenzweig and Jianchuan Gao and Hila Epstein and Irith Gati and Reuven Reich and Danenberg, {Haim D.} and Gershon Golomb",

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AU - Cohen-Sela, Einat

AU - Rosenzweig, Ohad

AU - Gao, Jianchuan

AU - Epstein, Hila

AU - Gati, Irith

AU - Reich, Reuven

AU - Danenberg, Haim D.

AU - Golomb, Gershon

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AB - Systemic transient depletion of monocytes and macrophages by liposome-encapsulated bisphosphonates (BPs), reduces neointimal formation in experimental restenosis. The aim of this study was to examine the antirestenotic effect of a polymeric nanoparticulate formulation containing the BP alendronate (ALN). The BP was successfully formulated in polylactide-co-glycolide (PLGA) nanoparticles (NP). ALN NP with negative charge, size of 223 ± 64 nm, and high entrapment efficiency (55.1%) have been formulated. ALN NP exhibited a significant cytotoxic effect, in a dose-response relationship, on macrophage-like RAW264 cells in cell culture. Subcutaneously (SC) administrated ALN NP (1.5 mg/kg on days - 1 and + 6) resulted in a significant attenuation of neointima to media ratio (N/M) by 52.7% and stenosis by 39.7% 28 days after balloon injury in the hypercholesterolemic rabbit model. Moreover, a good correlation was found between macrophage abundance in the injured arteries and the extent of stenosis. ALN NP treatment resulted in the reduction of both interleukin-1β and matrix metalloproteinases (2 and 9). It is concluded that a particulated dosage form of polymeric NP loaded with ALN reduce neointimal formation in vivo by systemic transient depletion of monocytes.

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KW - Immunomodulation

KW - Monocytes/macrophages

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Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis

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