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The onset and progression of liver diseases and cancer have shown to be affected by over-active macrophages and fibroblasts. Therefore, developing methods to suppress the activation of these cells has become an urgent task. Prior to this study, a mannosylated-albumin (Man-HSA) that targets mannose receptors expressed in hepatic macrophages (Kupffer cells) or fibroblasts was created. Here, we report on the development of medical treatments based on Man-HSA. To target the reactive oxygen species or inflammation derived from Kupffer cells, we developed a nano-antioxidant, i.e., polythiolated (SH)-Man-HSA, by introducing thiol groups into Man-HSA, or a nano-anti-inflammatory drug, i.e., Man-HSA-IFNα2b, by fusing Man-HSA and IFNα2b. SH-Man-HSA or Man-HSA-IFNα2b attenuated Kupffer cell-derived oxidative stress or inflammation, respectively, resulting in the suppression of liver damage and overall improvement of the survival rate in mice with acute and chronic liver injuries. Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF), both of which are present in the stroma of intractable cancers, also express mannose receptors. Thus, mono-polyethylene glycol modified Man-HSA (monoPEG-Man-HSA) was synthesized as a novel drug delivery carrier targeting TAM/CAF. A complex of monoPEG-Man-HSA with paclitaxel suppressed tumor growth by decreasing the number of TAM/CAF and the stroma area. For the present study, we focused on the mannose receptors expressed in macrophages and fibroblasts, and developed drug delivery carriers that target these cells. Considering the excellent drug-carrying capacity and high biocompatibility of HSA, it is expected that this research will pave the way for innovative pharmacotherapy to treat unmet medical needs, i.e., intractable liver diseases and cancer.

Candida albicans mannan consists of the α-1,6-linked backbone moiety and the α-1,2- and α-1,3-linked side chains. It also contains α-1,6-branched mannose units, β-1,2-linked mannose units, and phosphate groups. The cell wall mannans of the genus Candida possess three types of β-1,2 linked mannose units. One is linked via the phosphodiester linkage, the second type is connected to an α-1,2-linked mannose unit, and the third type is attached to an α-1,3-linked mannose unit. These β-1,2-linked mannose units showed a strong antigenicity and produce the characteristic NMR chemical shifts. Using two-dimensional NMR techniques, we will practically determine the structure of these polysaccharides in a nondestructive manner. [ABSTRACT FROM AUTHOR]

In the post-genome era, the analysis of disease-related genes has rapidly advanced, and the medical application of the information obtained from gene analysis is being put into practice. In particular, the development of a novel system to transfect the gene of interest selectively and efficiently into targeted cells is essential for the gene therapy of refractory diseases, in vivo functional analysis of genes, and establishment of animal models for diseases. However, a suitable carrier for selective gene delivery to targeted cells remains to be developed. The sonoporation method using microbubbles and ultrasound (US) exposure is one of the most promising approaches for effective gene transfection. However, it is difficult to transfect the therapeutic gene into the targeted organs/cells selectively by the conventional sonoporation method. Recently, our group has developed mannose-modified and US-responsive carriers/nucleic acid complexes (Man-PEG(2000) bubble lipoplexes), and succeeded in obtaining the enhanced and selective gene expression in mannose receptor-expressing cells by combination with US exposure. In this review, I described our gene transfection methods using Man-PEG(2000) bubble lipoplexes and external US exposure. Additionally, I also reviewed the enhancing mechanism of gene expression focusing on the intracellular transporting processes, in vivo distribution, and the activation of transcriptional factors. I believe that these findings help in the development of an effective gene transfection system using US-exposing system.

NFkappaB regulate several inflammatory related molecules and evoke immune and inflammatory response by several stimuli, therefore inhibition of NFkappaB activation would be a novel therapeutic strategy. To date, there are many conventional drugs including nonsteroldal or steroldal anti-inflammatory drugs or immune suppressors etc. were known to inhibit NFkappaB activation, however, several side effects were also reported. Recently, double stranded oligonucleotide including NFkappaB binding sequence, called NFkappaB decoy, was developed to prevent NFkappaB activation, which is powerful tool in a new class of anti-gene strategy for molecular therapy with low side effect. However, NFkappaB decoy is easily degraded by nuclease and rapidly excreted to urine, therefore it is necessary to develop carrier for NFkappaB decoy therapy. Here, we shall review delivery system for NFkappaB decoy and introduce our cell-selective delivery system for NFkappaB decoy using sugar decorated cationic liposomes.

Drug delivery systems (DDS) using liposomes as drug carriers for targeting to macrophages have been developed for the treatment of diseases that macrophages are related to their progress. Initially, DDS for the treatment of atherosclerosis are described. The influence of particle size on the drug delivery to atherosclerotic lesions that macrophages are richly present and antiatherosclerotic effects following intravenous administration of liposomes containing dexamethasone (DXM-liposomes) was investigated in atherogenic mice. Both the drug delivery efficacy of DXM-liposomes (particle size, 200 nm) to atherosclerotic lesions and their antiatherosclerotic effects were greater than those of 70 and 500 nm. These results indicate that there is an optimal particle size for drug delivery to atherosclerotic lesions. DDS for the treatment of respiratory infections are then described. The influence of particle size and surface mannosylation on the drug delivery to alveolar macrophages (AMs) and antibacterial effects following pulmonary administration of liposomes containing ciprofloxacin (CPFX-liposomes) was investigated in rats. The drug delivery efficacy of CPFX-liposomes to AMs was particle size-dependent over the range 100-1000 nm and then became constant at over 1000 nm. These results indicate that the most effective size is 1000 nm. Both the drug delivery efficacy of mannosylated CPFX-liposomes (particle size, 1000 nm) to AMs and their antibacterial effects were significantly greater than those of unmodified CPFX-liposomes. These results indicate that the surface mannosylation is useful method for drug delivery to AMs. This review provides useful information to help in the development of novel pharmaceutical formulations aimed at drug targeting to macrophages.