Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis

Cohen-Sela, Einat; Rosenzweig, Ohad; Epstein, H.; Gati, Irith; Reich, Reuven; Danenberg, Haim; Golomb, Gershon

doi:10.1016/j.jconrel.2006.03.010

Cited by 68 publications

(61 citation statements)

References 44 publications

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“…Long term inactivation of macrophages carries the danger of immunosuppression and infection. However, as in several studies in rabbits and rats, no overt infection was observed with partial and transient monocytes depletion (12)(13)(14)(15)(16)42,46,59).…”

Section: Discussionsupporting

confidence: 71%

“…Circulating blood monocytes fully recovered 7 days after injection. The effects of liposomal simvastatin are limited to cells with phagocytic capacity with no effect on other cells, such as SMC or endothelial cells, as has been demonstrated in animals treated with liposomal BPs (12)(13)(14)(15)(16)42,46). Simvastatin leaking from inactivated monocytes and the delivery system would accumulate mainly in the liver.…”

Section: Discussionmentioning

confidence: 95%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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Liposomal Simvastatin Attenuates Neointimal Hyperplasia in Rats

Afergan

David

Epstein

et al. 2010

AAPS J

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Abstract. Monocytes, macrophages, and inflammation play a key role in the process of neointimal proliferation and restenosis. The present study evaluated whether systemic and transient depletion of monocytes could be obtained by a single intravenous (IV) injection of simvastatin liposomes, for the inhibition of neointima formation. Balloon-injured carotid artery rats (n=30) were randomly assigned to treatment groups of free simvastatin, simvastatin in liposomes (3 mg/kg), and saline (control). Stenosis and neointima to media ratio (N/M) were determined 14 days following single IV injection at the time of injury by morphometric analysis. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Inhibition of RAW264.7, J774, and THP-1 proliferation by simvastatinloaded liposomes and free simvastatin was determined by the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay. Simvastatin liposomes were successfully formulated and were found to be 1.5-2 times more potent than the free drug in suppressing the proliferation of monocytes/ macrophages in cell cultures of RAW 264.7, J774, and THP-1. IV injection of liposomal simvastatin to carotid-injured rats (3 mg/kg, n=4) resulted in a transient depletion of circulating monocytes, significantly more prolonged than that observed following treatment with free simvastatin. Administration to ballooninjured rats suppressed neointimal growth. N/M at 14 days was 1.56±0.16 and 0.90±0.12, control and simvastatin liposomes, respectively. One single systemic administration of liposomal simvastatin at the time of injury significantly suppresses neointimal formation in the rat model of restenosis, mediated via a partial and transient depletion of circulating monocytes.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liposomal Simvastatin Attenuates Neointimal Hyperplasia in Rats

Afergan

David

Epstein

et al. 2010

AAPS J

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“…Elevated inflammatory markers such as total leukocyte count [3,4] and C-reactive protein levels [5,6] are associated with worse outcome after percutaneous coronary artery interventions (PCI). Suppression of innate immunity by various strategies alleviates the inflammatory response following injury and suppresses excessive reactivity, as evidenced by lesser degree of neointimal formation [7][8][9][10]. In contrast, events and phenomena that promote systemic inflammation, though not directly related to vascular injury, can exacerbate the reactivity to local vascular injury.…”

Section: Introductionmentioning

confidence: 99%

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

et al. 2008

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Background-Inflammation is important to vascular repair following injury, modulating neointimal proliferation and remodeling. Previously, we have shown that a low-intensity inflammatory response aggravates neointimal formation following balloon and stent injury. The present study examined whether modulation of the extent and timing of nonspecific inflammation mediates the local vascular response in an additive unidirectional or rather a bidirectional fashion.Methods and results-Rabbits subjected to denudation and balloon injury of the iliac artery were treated with low(1 µg/kg) or high (100µg/kg) doses of bacterial endotoxin (LPS) immediately after injury, or with early high-dose LPS administered 3 days prior to injury (preconditioning). Neointimal formation at 28 days was significantly increased in the low-dose group (0.537 ± 0.059mm 2 ) as compared with controls (0.3 ± 0.03mm 2 ). High-dose LPS did not significantly affect neointimal formation while early high dose significantly reduced neointima (0.296 ± 0.033 and 0.194 ± 0.025mm 2 , respectively, n = 12-14/group). Arterial wall and systemically circulating interleukin-1β levels, and monocyte CD14 activation correlated with neointimal formation. Vascular remodeling was accelerated in animals treated with low-or high-dose LPS while not affected in the preconditioned group. Remodeling index inversely correlated with arterial matrix metalloproteinase-2 levels 6 days after injury.Conclusions-The extent and timing of nonspecific inflammation that is concurrent with vascular injury can determine different and opposite vascular repair patterns.

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pH Tunable Fluorescent Calcium Phosphate Nanocomposite for Sensing and Controlled Drug Delivery

2010

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In this work, a novel pH sensitive calcium phosphate (CaP) nanocomposite capable of performing multiple tasks of controlled drug delivery, and simultaneous sensing by change in the fluorescence was fabricated. The nanocomposite was synthesized by encapsulating alendronate (AD) drug in CaP and modifying the surface with a fluorescent rhodamine B (RDB) dye. The multifunctional nanocomposite demonstrated high loading capacity for AD, excellent pH‐tunable AD release and optical sensing behavior, and good aqueous dispersity. Analysis by transmission electron microscopy and dynamic light scattering analysis revealed that RDB modified CaP/AD (RDB‐CaP/AD) nanocomposite had average dimensions of 21 nm × 44 nm and mean hydrodynamic size of 55 nm. The feasibility of CaP/AD nanocomposite for controlled drug delivery by pH responsive release was demonstrated by in vitro study at two different pH, 5.0 and 7.4. Furthermore, CaP/AD loaded with fluorescent RDB showed pH tunable fluorescence property, which can help in tracking the active state of the particle and give measurable indication of the drug delivery. In vitro study with osteoclast precursor cells, RAW 264.7 confirmed that CaP/AD nanocomposite significantly reduced the activity of osteoclast cells. The present study demonstrates that the fabricated multifunctional RDB‐CaP/AD nanocomposites can serve as an effective drug delivery vehicle capable of controlled drug release and sensing, simultaneously.

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Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis

Cited by 68 publications

References 44 publications

Liposomal Simvastatin Attenuates Neointimal Hyperplasia in Rats

Liposomal Simvastatin Attenuates Neointimal Hyperplasia in Rats

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

pH Tunable Fluorescent Calcium Phosphate Nanocomposite for Sensing and Controlled Drug Delivery

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