Targeted delivery of superoxide dismutase to macrophages via mannose receptor-mediated mechanism

Takakura, Yoshinobu; Masuda, Sada; Tokuda, Hideaki; Nishikawa, Makiya; Hashida, Mitsuru

doi:10.1016/0006-2952(94)90485-5

Cited by 47 publications

(11 citation statements)

References 24 publications

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“…In our series of investigations, we have systematically studied the pharmacokinetics of macromolecules at the whole body, organ, and cellular levels by employing in vivo tissue distribution (Takakura et al, 1990(Takakura et al, , 1994aKawabata et al, 1995), in situ organ perfusion (Imoto et al, 1992;Nishida et al, 1992;Mihara et al, 1993;Takakura et al, 1994c), and in vitro cellular uptake (Tokuda et al, 1993;Takakura et al, 1994b) experiments, respectively. These studies have clarified the pharmacokinetic properties of the macromolecules in relation to their physicochemical characteristics, such as molecular weight and electric charge.…”

Section: Discussionmentioning

confidence: 99%

Renal Disposition Characteristics of Oligonucleotides Modified at Terminal Linkages in the Perfused Rat Kidney

Sawai¹,

Miyao²,

Takakura³

et al. 1995

Antisense Research and Development

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To clarify the renal disposition characteristics of oligonucleotides at the organ level, the renal handling of model end-capped oligonucleotides, 3'-methoxyethylamine 5'-biotin-decathymidylic acid containing phosphoramidate modifications at 3'- and 5'-terminal internucleoside linkages (T10) and its phosphorothioate (Ts10), were studied in the perfused rat kidney. In a single-pass indicator dilution experiment, venous outflow and urinary excretion patterns and tissue accumulation of radiolabeled oligonucleotides were evaluated under filtering or nonfiltering conditions. No significant binding to bovine serum albumin (BSA) in the perfusate was observed for T10, whereas more than 90% of Ts10 bound to BSA. The steady-state distribution volume of T10 calculated from the venous outflow pattern was larger than that of inulin, which corresponds to the extracellular volume of the kidney, whereas the distribution volume of Ts10 was larger than that of BSA (the intravascular volume). These results suggested their interaction with the vascular wall. Rapid urinary excretion was observed for T10, similar to inulin used as a marker of golmerular filtration rate. On the other hand, urinary excretion of Ts10 was greatly restricted due to its high binding ability (> 90%) to BSA in the perfusate. A significant amount of T10 and Ts10 was accumulated in the kidney (T10, 1.8% of injected dose; Ts10, 1.3%) compared with inulin (0.2%) and BSA (< 0.1%). The accumulation of these oligonucleotides was ascribed to both tubular reabsorption and uptake from the capillary side. In addition, the uptake of T10 from the capillary side was significantly inhibited by simultaneous injection of dextran sulfate, suggesting that the oligonucleotide was taken up as an anionic molecule. These findings will be useful information for the development of delivery systems for antisense oligonucleotides.

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Section: Discussionmentioning

confidence: 99%

Renal Disposition Characteristics of Oligonucleotides Modified at Terminal Linkages in the Perfused Rat Kidney

Sawai¹,

Miyao²,

Takakura³

et al. 1995

Antisense Research and Development

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“…Similar results have been obtained by others with native CuZn SODs, and liposome-encapsulated or chemically modified (acylated) CuZn SODs penetrated into erythrocytes, lymphocytes, and neutrophils (6,7). We could not find any data on monocytes in the literature, except for a study of mouse peritoneal macrophages by Takamura et al (15) in which radiolabeled rh SOD was used in a mannosylated form. Beckman et al (16) reported a punctate distribution pattern of FITC-SOD in endothelial cells from porcine thoracic aorta that is very similar to that observed by us in monocytes.…”

Section: Discussionmentioning

confidence: 99%

Cellular Penetration of Fluorescently Labeled Superoxide Dismutases of Various Origins

Filipe¹,

Emerit²,

Vassy³

et al. 1999

Mol Med

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Background: Using fluorescently labeled superoxide dismutase (SOD) and flow cytometry, we have shown previously that the enzyme CuZn SOD (EC 1.15.1.1) from bovine erythrocytes binds rapidly to the cell surface with slow uptake into the cell during the following hours. The degree of labeling was most important for monocytes in comparison to other blood cells (erythrocytes, lymphocytes, and neutrophils) and fibroblasts. In agreement with the flowcytometric findings, the inhibition of superoxide production was more important for SOD-pretreated monocytes than for neutrophils, as demonstrated with the cytochrome c reduction assay. It was thus of interest to confirm the observed differences between monocytes and neutrophils with confocal laser microscopy, study in greater detail the kinetics of binding, penetration, and intracellular localization of the enzyme, and compare the results obtained with bovine CuZn SOD with those from SODs of other origins and carrying different active sites. Materials and Methods: Recombinant human (rh), bovine, and equine CuZn SODs, as well as rh and E. coli Mn SODs, were studied before use with respect to specific activity and purity (HPLC, SDS-PAGE electrophoresis). Fluorescein isothiocyanate was covalently conjugated to the various SODs for study with high-resolution confocal scanning laser microscopy. Superoxide production by monocytes and neutrophils was measured with the cytochrome c assay. Results: As expected from our experiments with flow cytometry, only rare neutrophils were labeled with FITC-SOD, even with the longest incubation time of 3 hr and the highest dose of 1500 units/ml. In addition, they showed a localized fluorescence pattem that was quite different from the diffuse punctate fluorescence pattern of monocytes. Lymphocytes were not labeled at all. The rapid binding to the cellular surface of monocytes was confirmed, and even after 5 min of preincubation, FITC-SOD was found on a small percentage of monocytes. This was correlated with a reduction in superoxide release after phorbolmyristate acetate (PMA) stimulation by 40%. An interesting finding was the perinuclear accumulation of the penetrated SOD after the longest pretreatment of 3 hr, suggesting a baffier against further progression. Indeed, through confocal niicroscopy we were able to excdude any fluorescence at the nudear level. While the fluorescence labeling patterns and the kinetics of penetration were quite similar for bovine, equine, and rh CuZn SOD, the Mn SODs showed poor labeling, correlated with a weak inhibitory effect on cytochrome c reduction, which was not statistically significant. Conclusions: The rapid binding of native CuZn SODs on the surface of monocytes, leading to reduced superoxide release by these cells, explains the observation that beneficial effects of injected SOD lasted for months despite rapid dearance of the enzyme from the bloodstream, according to pharmacodynamic studies. The preferential binding to monocytes, in contrast to neutrophils, may play a role in chronic inflammatory disea...

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“…For example, the mannosylation of enzymes has allowed the targeting of enzymes to particular diseased cells. Replacement β-glucocerebrosidase, an enzyme which is lacking in Gaucher disease, 265 and the beneficial anti-oxidant effects of superoxide dismutase (SOD) 266 have both been directed to macrophages. SOD has also been conjugated with sodium hyaluronate, a polymer of the dimeric motif GlcNAc-glucuronic acid.…”

Section: Other Therapeutic Strategiesmentioning

confidence: 99%

Recent developments in glycoconjugates

Davis

1999

J. Chem. Soc., Perkin Trans. 1

160

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Targeted delivery of superoxide dismutase to macrophages via mannose receptor-mediated mechanism

Cited by 47 publications

References 24 publications

Renal Disposition Characteristics of Oligonucleotides Modified at Terminal Linkages in the Perfused Rat Kidney

Renal Disposition Characteristics of Oligonucleotides Modified at Terminal Linkages in the Perfused Rat Kidney

Cellular Penetration of Fluorescently Labeled Superoxide Dismutases of Various Origins

Recent developments in glycoconjugates

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