The influence of particle size and surface mannose modification on the uptake of liposomes by alveolar macrophages (AMs) was investigated in-vitro and in-vivo. Non-modified liposomes of five different particle sizes (100, 200, 400, 1000 and 2000 nm) and mannosylated liposomes with 4-aminophenyl-alpha-D-mannopyranoside (particle size 1000 nm) were prepared, and the uptake characteristics by rat AMs in-vitro and in-vivo were examined. The uptake of non-modified liposomes by rat AMs in-vitro increased with an increase in particle size over the range of 100-1000 nm, and became constant at over 1000 nm. The uptake of non-modified liposomes by AMs after pulmonary administration to rats in-vivo increased with an increase in particle size in the range 100-2000 nm. The uptake of mannosylated liposomes (particle size 1000 nm) by rat AMs both in-vitro and in-vivo was significantly greater than that of non-modified liposomes (particle size 1000 nm). The results indicate that the uptake of liposomes by rat AMs is dependent on particle size and is increased by surface mannose modification.

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In order to confirm the efficacy of ciprofloxacin (CPFX) incorporated into liposomes (CPFX-liposomes) for treatment of respiratory intracellular parasite infections, the influence of particle size on drug delivery to rat alveolar macrophages (AMs) following pulmonary administration of CPFX-liposomes was investigated. CPFX-liposomes were prepared with hydrogenated soybean phosphatidylcholine (HSPC), cholesterol (CH) and dicetylphosphate (DCP) in a lipid molar ratio of 7/2/1 by the hydration method and then adjusted to five different particle sizes (100, 200, 400, 1000 and 2000 nm). In the pharmacokinetic experiment, the delivery efficiency of CPFX to rat AMs following pulmonary administration of CPFX-liposomes increased with the increase in the particle size over the range 100-1000 nm and became constant at over 1000 nm. The concentrations of CPFX in rat AMs until 24 h after pulmonary administration of CPFX-liposomes with a particle size of 1000 nm were higher than the minimum inhibitory concentration of CPFX against various intracellular parasites. In a cytotoxic test, no release of lactate dehydrogenase (LDH) from rat lung tissues by pulmonary administration of CPFX-liposomes with a particle size of 1000 nm was observed. These findings indicate that efficient delivery of CPFX to AMs by CPFX-liposomes with a particle size of 1000 nm induces an excellent antibacterial effect without any cytotoxic effects on lung tissues. Therefore, CPFX-liposomes may be useful in the development of drug delivery systems for the treatment of respiratory infections caused by intracellular parasites, such as Mycobacterium tuberculosis, Chlamydia pneumoniae and Listeria monocytogenes.

Sonophoresis is a physical technique to enhance transdermal delivery of various drugs using ultrasound energy.1,2) A wide range of frequencies (20 kHz-16 MHz) have been used for sonophoresis. [3][4][5] In the recent studies, lowfrequency ultrasound (20-100 kHz) has been shown to be more potent in enhancing transdermal delivery compared with high-frequency ultrasound (more than 2 MHz). We previously reported that low-frequency and low-intensity ultrasound (41 kHz, 120 mW/cm 2 ) was able to increase the permeation of calcein (hydrophilic model solute, MW 623) and water vehicle across excised hairless rat skin. 6) Our results suggested that potential inductions of alterations of the skin barrier properties by ultrasound application and convection specifically occurring during ultrasound application were responsible for the sonophoretic enhancement. However, it is not clear how ultrasound causes such skin alteration and convection across the skin.Several physical events accompanied by ultrasound application, including thermal effects, radiation pressure, and acoustic cavitation, can contribute to sonophoretic enhancement.7) These physical events may affect the permeation properties of the skin directly and indirectly. Bommannan et al. have demonstrated that the enhancing effect of sonophoresis induced by high-frequency ultrasound (10 MHz, 16 MHz) may be attributed to the direct actions of ultrasound presumably due to cavitational effects in the stratum corneum. 3,8) In contrast, skin conductivity enhancement induced by low-frequency sonophoresis (20 to 100 kHz) can be related to indirect actions, such as mechanical impact, due to the collapse of cavitation bubbles in solution, resulting in disruption of the structure of lipid bilayers in the stratum corneum.9,10) In addition, the indirect cavitational effect (collapse of cavitation bubbles in the solution) can generate forced convection in the presence of ultrasound. 11)Acoustic cavitation can be broadly classified as either stable cavitation which corresponds to steady oscillations of bubbles or transient (inertial) cavitation which corresponds to a rapid growth followed by a rapid collapse.7) Findings obtained by Tezel et al. emphasize the importance of transient cavitation at low-frequencies (20-100 kHz), because the amplitude of broadband noise induced by the transient cavitation correlated well with the enhanced skin conductivity. 12)Cavitation collapses at two different locations in the solution give different patterns. Symmetric (isotropic) collapses of transient cavitation in the bulk solution away from the skin surface result in several physical events, such as localized high pressures, a thermal effect, and emitted shock waves. 7)In contrast, asymmetric (anisotropic) collapses in the solution close to the skin surface induce movement of the liquid microjet to the surface with a velocity of up to 100 m/s. 13,14) Kodama and Tomita verified liquid microjet formation in 10-30% hard gelatin gels using high-speed photography. 15)Therefore, indirect actions, such...