Growth Inhibition of Macrophage-like and Other Cell Types by Liposome-encapsulated, Calcium-bound, and Free Bisphosphonates<i>In Vitro</i>

Mönkkönen, Jukka; Taskinen, Markku; Auriola, Seppo; Urtti, Arto

doi:10.1080/10611860310001636539

Cited by 27 publications

(37 citation statements)

References 27 publications

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“…The effect of LBP treatment on proliferating SMCs, which compose the major component of human restenotic lesions, is indirectly mediated via the inhibitory effect on macrophages; in vitro studies showed unequivocally that macrophages are much more sensitive 5,18 to LBPs than SMCs. The reduction in SMC proliferation and content supports the major role of monocytes in neointimal formation after stent injury and the potential use of macrophage depletion in its modulation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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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

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Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…The concentration of the drug was determined in all fractions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) as an additional measure of vesicle integrity (Fig. 2, middle column).…”

Section: Liposome Integrity In Serum In Vitromentioning

confidence: 99%

“…The formulation of alendronate liposomes examined so far by our group (2,3) was of a wide range of size distribution (100 to 500 nm, with fractions >1 μm), the process was not always reproducible, shelf life stability was less than 1 month, and could not be easily up-scaled for manufacturing (14). All liposomal bisphosphonate formulations reported heretofore were prepared by the reverse-phase evaporation (REV) method (1,10,(15)(16)(17) or the evaporation technique (18,19); encapsulation yield was low (3% and 5-7%, for alendronate (20) and clodronate liposomes (19), respectively), stability in vitro was less than 1 month (19,20), in vivo stability had not been determined, liposome size was characterized with a wide-size distribution (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and filter-sterilization was impossible.…”

Section: Introductionmentioning

confidence: 99%

Preparation of Alendronate Liposomes for Enhanced Stability and Bioactivity: In Vitro and In Vivo Characterization

Epstein

Gutman

Cohen-Sela

et al. 2008

AAPS J

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Abstract. Liposomes containing bisphosphonates have been shown to deplete circulating monocytes and reduce experimental restenosis. However, acceptable shelf life was not achieved, and the disruption extent and rate of the vesicles in the circulation has not been examined. Designing an optimal liposomal formulation in general, and for an anti-inflammatory effect in particular, requires careful consideration of the factors that contribute to their in vitro stability and integrity in the blood after injection. An improved liposomal alendronate formulation was prepared by a modified thin lipid film hydration technique followed by extrusion, resulting in relatively smaller size vesicles, narrow size distribution, and low drug to lipid ratio in comparison to the reverse phase evaporation method. In order to rule out premature leakage of the drug, the integrity of the vesicles was examined by means of size-exclusion chromatography in vitro and in vivo, with subsequent analysis of size, drug (fractions of encapsulated and free) and lipid concentrations. Vesicles were found to be stable in serum, with 15±3% leakage of the drug after 10 min in rabbit's circulation, and intact liposomes were detected in the circulation 24 h following administration. It is concluded that the new formulation results in increased stability (2.5 years) as determined by the insignificant changes in vesicle size, drug leakage, lipid and drug stability, in vitro bioactivity (macrophages inhibition), as well as in vivo in depleting circulating monocytes and inhibition of restenosis in rabbits. Our in vitro stability results regarding dilution in serum paralleled in vivo data. Thus, in vitro assessment may provide a valuable tool in assessing in vivo integrity of liposomal formulations.

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“…58 Although free DMDP is a highly hydrophilic drug that hardly crosses the cellular phospholipid membrane, we successfully decreased the amount of microglia in our setup ( Figure 4A and B). 59 Compared to the control, DMDP-treated specimens showed increased tissue degeneration at 9 DIV but no further alteration until 11 DIV (Figure 4M-P).…”

mentioning

confidence: 91%

Biocompatibility of very small superparamagnetic iron oxide nanoparticles in murine organotypic hippocampal slice cultures and the role of microglia

Pohland

Glumm

Wiekhorst

et al. 2017

IJN

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Superparamagnetic iron oxide nanoparticles (SPIO) are applied as contrast media for magnetic resonance imaging (MRI) and treatment of neurologic diseases despite the fact that important information concerning their local interactions is still lacking. Due to their small size, SPIO have great potential for magnetically labeling different cell populations, facilitating their MRI tracking in vivo. Before SPIO are applied, however, their effect on cell viability and tissue homoeostasis should be studied thoroughly. We have previously published data showing how citrate-coated very small superparamagnetic iron oxide particles (VSOP) affect primary microglia and neuron cell cultures as well as neuron-glia cocultures. To extend our knowledge of VSOP interactions on the three-dimensional multicellular level, we further examined the influence of two types of coated VSOP (R1 and R2) on murine organotypic hippocampal slice cultures. Our data show that 1) VSOP can penetrate deep tissue layers, 2) long-term VSOP-R2 treatment alters cell viability within the dentate gyrus, 3) during short-term incubation VSOP-R1 and VSOP-R2 comparably modify hippocampal cell viability, 4) VSOP treatment does not affect cytokine homeostasis, 5) microglial depletion decreases VSOP uptake, and 6) microglial depletion plus VSOP treatment increases hippocampal cell death during short-term incubation. These results are in line with our previous findings in cell coculture experiments regarding microglial protection of neurite branching. Thus, we have not only clarified the interaction between VSOP, slice culture, and microglia to a degree but also demonstrated that our model is a promising approach for screening nanoparticles to exclude potential cytotoxic effects.

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Growth Inhibition of Macrophage-like and Other Cell Types by Liposome-encapsulated, Calcium-bound, and Free BisphosphonatesIn Vitro

Cited by 27 publications

References 27 publications

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

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

Preparation of Alendronate Liposomes for Enhanced Stability and Bioactivity: In Vitro and In Vivo Characterization

Biocompatibility of very small superparamagnetic iron oxide nanoparticles in murine organotypic hippocampal slice cultures and the role of microglia

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