Mika Shinohara

Tokushima University

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Hiroshi Kiwada

Tokushima University

Tatsuhiro Ishida

Tokushima University

Hideyoshi Harashima

Hokkaido University

Fusako Iwata

Otsuka (Japan)

Abu J Ferdous

Florida Agricultural and Mechanical University

Yasukazu Ohmoto

Tokushima University

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Tokushima University

Otsuka (Japan)

Otsuka Pharmaceutical (Spain)

Kyoto University

Nihon University

Kumamoto University

Jikei University School of Medicine

Hokkaido University

Hokkaido Pharmaceutical University

Assiut University

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Quantitative determination of C3 fragments on the liposomal surface with anti-human C3 monoclonal antibodies.

Drug Delivery System (1994)

Tatsuhiro Ishida Mika Shinohara Fusako Iwata Yasukazu Ohmoto Hiroshi Kiwada

Quantitative determination of human complement component 3 (C3) fragments on the liposomal surface is considered to give useful informations for speculation of the biological fate of liposomes. The determination method of C3 fragments on the liposomal surface with anti-human C3 monoclonal antibodies (MoAbs) is presented in this paper. Twelve MoAbs(KOCO2831∼2812) were prepared and two-site sandwich enzyme-linked immunospecific assay(Sandwich-ELISA) system was developed. It became apparent all antibodies obtained in this study recognize β-chain of C3 structure. KOCO2801 and biotinylated KOCO2804 gave an optimal combination for the ELISA system. C3 fragments bound to surface of cetyimannoside-modified liposome (Man-MLV) and non-modified liosomes (PC-MLV) were determined after incubation with fresh human plasma. After separation of liposomes from the plasma by centrifugation, lipids were removed by extraction with 1, 1, 2-Trichloro-1, 2, 2-trifluoroethane, and then C3 fragments were determined in the ELISA system. The results showed that C3 bound on the Man-MLV are more larger quantities than those of PC-MLV, This result confirmed that the ammount of C3 bound on liposomal surface correlates with the instability of the liposomes in the circulation and the enhancing hepatic uptake of the liposomes. Thus, this approach can be available for investigation of liposomal behaviour in the circulation.

10.2745/dds.9.25

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SIZE-DEPENDENT RELEASE OF CARBOXYFLUORESCEIN FROM CETYLMANNOSIDE-MODIFIED LIPOSOMES IN HUMAN PLASMA

Biopharmaceutics & Drug Disposition (1996)

Abu J Ferdous Tatsuhiro Ishida Mika Shinohara Hideyoshi Harashima Hiroshi Kiwada

The interaction of liposomes with human plasma was investigated using 6(5)-carboxyfluorescein (CF) as an aqueous phase marker of cetylmannoside-modified multilamellar vesicles (Man-MLVs) of various sizes. The release of CF decreased with increasing liposome concentration. The time courses of the CF release from Man-MLVs were monitored continuously and were analysed kinetically. The curves were characterized by two phases, the first-order release process and the maximum release, which represent the rate and the extent of CF release, respectively. The increase of liposome size increased the rate of release by 42% and the extent of release by 121%, respectively. These effects of liposome size on the release processes were suggested to result from the size-dependent affinities of liposomes to the human complement system. The assay system of liposomally bound fragments of complement component 3 (C3), such as C3b and/or iC3b, was developed by applying a sandwich enzyme-linked immunospecific assay. The percentage of C3 fragments to total proteins bound to liposomes increased with the size of liposomes and there was a good correlation between the extent of CF release and the percentage of C3 fragments bound. These results indicated that Man-MLVs released entrapped CF via activating the human complement system and the affinity of Man-MLV to complement increased with the size of Man-MLVs in human plasma. These in vitro results suggest the role of complement as an opsonin in the disposition of Man-MLVs in humans.

10.1002/(sici)1099-081x(199603)17:2<145::aid-bdd942>3.0.co;2-y

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Effect of liposome sizes on binding of C3 fragments to cetylmannoside-modified liposomes in human.

Drug Delivery System (1997)

Tatsuhiro Ishida Mika Shinohara Hiroshi Kiwada

In order to reveal quantitatively interaction of complement (C) system with liposomes, we determined C3 fragments associated with the liposomes having different sizes after incubation in human plasma. The amount of C3 fragments per unit surface area on the unstable liposomes (Man-liposomes) which modified with synthesized glycolipid (cetylmannoside, Man) increased with the increase in the liposome size, whereas that of C3 fragments on the stable ones (PC-liposomes) was little found. In addition, the instability of Man-liposomes also increased with the increase in the liposome size and there was linear correlation. On the other hand, the amount of bound plasma proteins per unit surface area of liposomes was approximately constant regardless of differences of lipid composition and size, and showed no correlation with instability of the liposomes in the plasma. These in vitro results indicate that the instability of Man-liposomes is governed by the affinity of C system and the C system can recognize not only liposome surface characteristics but also liposome sizes. To demonstrate clearly the reason for the linear correlation between the affinity of C system and liposome size, we discussed the underlying mechanism based on the previous finding that the activation of C system by Man-MLVs was enhanced through classical C pathway and presented the hypothesized osculating model on the assumption that extent of C activation is governed by attachment of a C activator.

10.2745/dds.12.155

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Citations (2)