The object of our work is to define the possible role of hypotonically loaded erythrocytes as carriers to target drugs to the reticuloendothelial system. We have examined choices of drugs for loading into the erythrocytes and have considered methods of altering potentially useful agents so that they will load. We have demonstrated that the delivery of bleomycin to the reticuloendothelial system of mice, inside erythrocyte carriers, potentiates the effect of this drug on phagocytosis. We speculate, that this targeted delivery of bleomycin to phagocytes could be beneficial in the treatment of diseases characterized by an important phagocytic component.
In iron overload resulting from repeated blood transfusion, phagocytic reticuloendothelial cells are the primary and major sites of iron accumulation. Removal of this iron by the iron chelator deferoxamine can be enhanced by targeted delivery of this agent to reticuloendothelial cells. We have used resealed erythrocyte ghosts as a model system for delivery of deferoxamine to reticuloendothelial cells and have demonstrated a several-fold enhancement of urine iron excretion in children and adults with congenital or acquired iron-loading anemias. Although presently not cost-effective, this approach provides a useful, practical and safe model for [1] iron chelator targeting to reticuloendothelial cells, and [2] the clinical use of resealed erythrocyte ghosts for targeting pharmacologic agents to reticuloendothelial cells.
Radiolabeled DNA fragments or nuclear proteins were encapsulated within human erythrocytes, and the erythrocytes were then fused with cultured mammalian cells using Sendai virus. Autoradiography revealed that 125I-labeled DNA fragments remained dispersed in the cytoplasm and disappeared with a half-life of 24 hours. In contrast, the nuclear proteins, HMG1, HMG2, HMG17 and histone H1, rapidly localized within HeLa nuclei and exhibited half lives greater than 80 hours. Several biochemical criteria indicate that the association of the injected nuclear proteins with chromatin faithfully mimics the behavior of their endogenous counterparts.
Electric pulses in the range of 1 to 5 kV/cm and of durations 1 to 200 microseconds have been used to open up pores of limited size in various cell types. In the case of erythrocytes, these pores were shown to admit molecules as large as tetrasaccharides. Loading of clinically active drugs has also been attempted. Erythrocytes loaded with drugs can be resealed without loss of the hemoglobin content. With mouse erythrocytes, we have demonstrated the feasibility of using erythrocytes (not hemoglobin depleted ghosts) as drug carriers for prolonging the drug level in the circulation. Other possible applications of the method are also discussed.
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