Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats
Introduction
Today, pulmonary conditions including inflammation and infectious diseases are critical health problem. Alveolar macrophages are key effector cells in the first-line host defense [18] and lung homeostasis [27]. Pulmonary delivery via inhalation, non-invasive administration for local [7] and systemic effects [3], offers optimal bioavailability by reducing first-pass metabolism in the liver, reducing side effects, and improving patient compliance. Therefore, much effort has been directed toward the development of cell-selective targeting systems to macrophages using a variety of carriers to improve therapeutic efficiency and minimize side effects [13], [26], [30].
Liposomes have been considered as a potential drug and/or gene carrier due to enabling the loading capacity for a variety of compounds, allowing chemical modification for a wide range of applications, minimizing the systemic toxicity of the incorporated drugs and improving their stability [9], [11], [12], [21], [30]. Since mannose receptors, a 175 kDa transmembrane protein of the C-type lectin family, are exclusively expressed on the surface of alveolar macrophages that can recognize mannose terminal molecules with high affinity [14], mannosylation of liposomes is an attractive approach for cell-selective targeting to alveolar macrophages. We have previously reported macrophage-selective targeting by mannosylated liposomes (Man-liposomes) composed of novel mannosylated cholesterol derivatives, cholesten-5-yloxy-N-(4-((1-imino-2-d-thiomannosylethyl)amino)butyl)formamide (Man-C4-Chol), as a ligand for mannose receptors [12]. After intravenous administration to mice, Man-liposomes are rapidly and preferentially delivered to the hepatic non-parenchymal cells including Kupffer cells, via mannose receptor-mediated uptake [11], [12], [21]. However, targeting efficiency of Man-liposomes to alveolar macrophages by intratracheal administration could not be predicted. These observations prompted us to investigate whether Man-liposomes has a great potential as alveolar macrophage-selective targeting carriers administered via inhalation.
It has been reported that the efficient uptake of carrier systems is affected by the ligand density [34] and physiological environment [1], [28], [29]. A pulmonary surfactant (PS) composed of phospholipids (90%) and proteins (10%) is secreted as multilamellar assemblies from alveolar epithelial type II cells and is removed by alveolar epithelial type II cells and alveolar macrophages in order to obtain homeostasis [22]. PS, especially surfactant proteins, has been demonstrated to intercalate in the liposomal membrane [31] leading to leakage of encapsulated substances [1], [29], to alter the uptake of liposomes by alveolar cells [23] and reduce the efficiency of gene transfer [28].
The aim of this study was to evaluate the targeting efficiency of Man-liposomes to alveolar macrophages by direct pulmonary delivery. Man-liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), Cholesterol (Chol) and Man-C4-Chol with different molar ratios were characterized in a series of in vitro and in vivo studies. In vitro uptake of Man-liposomes was investigated in primary cultured rat alveolar macrophages. In vivo targeting of Man-liposomes was also studied after intratracheal administration in rats.
Section snippets
Materials
DSPC and sulforhodamine B were purchased from Sigma-Aldrich, Co. (St. Louis, MO, USA). N-(fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt (fluorescein DHPE, F-DHPE) was obtained from Molecular Probes, Inc. (Eugene, OR, USA). Rhodamine Concanavalin A conjugate (RhoConA), maclura pomifera agglutinin (MPA) biotinylated lectins and Texas Red steptavidin were provided by Vector Laboratories, Inc. (Burlingame, CA, USA). Griffonia simplicifolia
Particle size of liposomes and in vitro uptake study
Among the various ratios of Man-C4-Chol containing liposomes, the mean particle size and zeta potential of liposomes ranged 90–125 nm with 0.14–0.35 polydispersity index and − 9 to 15 mV, respectively.
To characterize the in vitro uptake of fluorescent-labeled Man-liposomes in alveolar macrophages, the cells were subjected to various conditions involving different doses, temperatures and incubation times. The uptake of Man-7.5- and Man-5.0-liposomes was markedly higher than that of Man-2.5- and
Discussion
The purpose of this study was to assess the targeting efficiency of Man-liposomes to alveolar macrophages. This is the first study reporting the successful delivery of Man-liposomes, in terms of internalization, to alveolar macrophages via intratracheal administration since internalization is a crucial factor affecting the efficiency of delivery systems.
To evaluate the uptake and internalization characteristics of Man-liposomes via the mannose receptor-mediated mechanism in alveolar
Conclusions
We have demonstrated the efficient targeting to alveolar macrophages of Man-liposomes by increasing the mannose residues expressed on the surface of liposomes. Man-liposomes with a high content of Man-C4-Chol exhibit high affinity for mannose receptors resulting in extensive uptake by alveolar macrophages after intratracheal administration. In addition, Man-liposomes are moderately stable to prevent the release of incorporated drugs in lung microenvironment. These observations suggest that
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by Health and Labour Sciences Research Grants for Research on Advanced Medical Technology from the Ministry of Health, Labour and Welfare of Japan.
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