Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Abstract

Inhalation of bacterial endotoxin induces pulmonary inflammation by activation of nuclear factor B (NFB), production of cytokines and chemokines, and neutrophil activation. Although glucocorticoids are the drugs of choice, administration of free drugs results in adverse effects as a result of a lack of selectivity for the inflammatory effector cells. Because alveolar macrophages play a key role in the inflammatory response in the lung, selective targeting of glucocorticoids to alveolar macrophages offers efficacious pharmacological intervention with minimal side effects. We have demonstrated previously the selective targeting of mannosylated liposomes to alveolar macrophages via mannose receptor-mediated endocytosis after intratracheal administration. In this study, the anti-inflammatory effects of dexamethasone palmitate incorporated in mannosylated liposomes (DPML) at 0.5 mg/kg via intratracheal administration were investigated in lipopolysaccharide-induced lung inflammation in rats. DPML significantly inhibited tumor necrosis factor ␣, interleukin-1␤, and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration and myeloperoxidase activity, and inhibited NFB and p38 mitogen-activated protein kinase activation in the lung. These results prove the value of inhaled mannosylated liposomes as powerful targeting systems for the delivery of anti-inflammatory drugs to alveolar macrophages to improve their efficacy against lung inflammation. Inhalation of lipopolysaccharide (LPS), which is a component of Gram-negative bacteria presenting as an environment pollutant, contributes to inflammation in the lung. The downstream signaling pathways after LPS stimulation include the activation of alveolar macrophages, which are key effector cells to release proinflammatory cytokines including tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤) (Ulich et al., 1991), chemokines such as cytokine-induced neutrophil chemoattractant-1 (CINC-1) (Ulich et al., 1995), and activation of nuclear factor B (NFB) and p38 mitogen-activated protein kinase (p38MAPK). Thereafter, neutrophils are recruited into the lung and release protease enzymes, which trigger lung injury. Corresponding to these studies, depletion of alveolar macrophages by liposomal clodronate treatment completely suppressed the downstream signaling after LPS stimulation (Koay et al., 2002). These results indicate that alveolar macrophages play a key role in the inflammation to release proinflammatory cytokines and chemokines after LPS stimulation.Glucocorticoids (GCs) are the drugs of choice for treatment of lung inflammation via systemic or local administration. Although inhalation of free GC is a promising therapy with less systemic toxicity, the therapeutic efficacy has been ques-

Glycosylation-mediated targeting of carriers

“…The dimannosylated ligands were recognized as efficiently as tetramannosylated lipids by mannose receptors expressed on immature human dendritic cells. Man-C4-Chol contents in mannosylated liposomes enhanced the uptake of mannosylated liposomes from 2.5 to 7.5% (mol) by mannose receptor-mediated endocytosis in cultured rat alveolar macrophages [202]. This finding is in line with our previous report using mannosylated emulsion in mouse peritoneal macrophages [206].…”

“…formamide (Man-C4-Chol), a galactosylated cholesterol derivative, to prepare mannosylated liposomes [179]. To deliver drugs into macrophage-and/or dendritic cell in various tissues, we investigated various administration routes including intravenous [179,[192][193][194][195][196][197], intraperitoneal [198][199][200][201], and intratracheal [202,203] administration.…”

“…Examples of drug delivery or imaging applications by encapsulation of muramyl dipeptide [193], stavudine [184], dexamethasone palmitate [202], cytidine 5' diphosphocholine [187], amphotericin B [189], 64 Cu [191], and indocyanine green [206] have been reported. Similarly, encapsulation of various peptides to induce cytotoxic T lymphocytes for vaccination have been investigated [178,204,205].…”

‘Smart‘ non-viral Delivery Systems for Targeted Delivery of RNAi to the Lungs

“…Ligands such as antibodies for example anti-CC531 antibodies [111], polysaccharides such as O-stearyl amylopectin (O-SAP), glycolipids such as Man3-DPPE and mannosylated cholesterol (Mann-C4-Chol) [112][113][114], peptides such as Arg-Gly-Asp (RGD) [115] and glycoproteins can be incorporated into liposome formulations for macrophage targeting. Hasida and colleagues have evaluated mannosylated liposomes targeting macrophages and DCs for the delivery of anti-inflammatory agents such as dexamethasone palmitate (dex) [116] and NFκB decoy and anti-cancer agents including CpG oligonucleotides and DNA [117]. Intratracheally administered Man-C4-Chol liposomes were shown to be preferentially taken up by alveolar macrophages mediated via macrophage mannose receptors.…”

Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

“…Such decorations include peptides, 7 antibodies, 8 proteins, and sugars 9 that engage cell-specific receptors or facilitate phagocytosis. Outcome measures for improved ARV distribution are required beyond testing of plasma drug levels.…”