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Abstract
OX7 monoclonal antibody F(ab′)2 fragments directed against Thy1.1 antigen can be used for drug targeting by coupling to the surface of drug-loaded liposomes. Such OX7-conjugated immunoliposomes (OX7-IL) were used recently for drug delivery to rat glomerular mesangial cells, which are characterized by a high level of Thy1.1 antigen expression. In the present study, the relationship between OX7-IL tissue distribution and target Thy1.1 antigen localization in different organs in rat was investigated.
Western blot and immunohistofluorescence analysis revealed a very high Thy1.1 expression in brain cortex and striatum, thymus and renal glomeruli. Moderate Thy1.1 levels were observed in the collecting ducts of kidney, lung tissue and spleen. Thy1.1 was not detected in liver and heart. There was a poor correlation between Thy1.1 expression levels and organ distribution of fluorescence- or 14C-labeled OX7-IL. The highest overall organ density of OX7-IL was observed in the spleen, followed by lung, liver and kidney. Heart and brain remained negative. With respect to intra-organ distribution, a localized and distinct signal was observed in renal glomerular mesangial cells only. As a consequence, acute pharmacological (i.e. toxic) effects of doxorubicin-loaded OX7-IL were limited to renal glomeruli. The competition with unbound OX7 monoclonal antibody F(ab′)2 fragments demonstrated that the observed tissue distribution and acute pharmacological effects of OX7-IL were mediated specifically by the conjugated OX7 antibody. It is concluded that both the high target antigen density and the absence of endothelial barriers are needed to allow for tissue-specific accumulation and pharmacological effects of OX7-IL. The liposomal drug delivery strategy used is therefore specific toward renal glomeruli and can be expected to reduce the risk of unwanted side effects in other tissues.
| Abbreviations | ||
| DOPE | = | dilinoleoyl-glycero-phosphoethanolamine |
| DSPE | = | distearoyl-phosphatidyl-ethanolamine |
| DSPE–PEG | = | DSPE conjugated to polyethyleneglycol |
| FITC | = | fluorescein isothiocyanate |
| OEG | = | octaethylene glycol monododecyl ether |
| OX7 mAb | = | anti-Thy1.1 OX7 monoclonal antibody |
| OX7 F(ab′)2 | = | F(ab′)2 fragments of the OX7 monoclonal antibody |
| OX7-IL | = | OX7 F(ab′)2 -conjugated immunoliposomes |
| PC | = | phosphatidylcholine |
| RMC | = | rat mesangial cells |
| Thy1.1 | = | allelic variant 1.1 of the thymocyte differentiation marker 1 |
| Abbreviations | ||
| DOPE | = | dilinoleoyl-glycero-phosphoethanolamine |
| DSPE | = | distearoyl-phosphatidyl-ethanolamine |
| DSPE–PEG | = | DSPE conjugated to polyethyleneglycol |
| FITC | = | fluorescein isothiocyanate |
| OEG | = | octaethylene glycol monododecyl ether |
| OX7 mAb | = | anti-Thy1.1 OX7 monoclonal antibody |
| OX7 F(ab′)2 | = | F(ab′)2 fragments of the OX7 monoclonal antibody |
| OX7-IL | = | OX7 F(ab′)2 -conjugated immunoliposomes |
| PC | = | phosphatidylcholine |
| RMC | = | rat mesangial cells |
| Thy1.1 | = | allelic variant 1.1 of the thymocyte differentiation marker 1 |