Erythrocytes May Become Drug Delivery System
The research team, which summarized its ongoing work in a June issue of Gene Therapy, uses a special apparatus to load dexamethasone-21-phosphate into patients' erythrocytes, which convert the prodrug into dexamethasone. After encapsulation of the prodrug, which does not leak through the erythrocyte membrane, the cells are returned to the patients. As the erythrocytes convert dexamethasone-21-phosphate to dexamethsone, a steady supply of the drug leaks into the bloodstream.
So far, this method of drug delivery has produced a week to a month of detectable amounts of dexamethasone in patients with chronic obstructive pulmonary disease (PDF) or cystic fibrosis. Coincident with this therapy, the patients' health generally improved.
To encapsulate the prodrug into erythrocytes, the researchers dialyze the cells against a hypotonic sodium chloride solution, which enlarge the pores on the cells' surface enough to permit the entry of dexamethasone-21-phosphate. The pores are then closed by restoring the cells to a normal osmotic state, and unencapsulated drug is washed away.
According to the researchers, the encapsulation process is mostly automated through the use of a machinedubbed the "Red Cell Loader"that consists mainly of a centrifuge, vacuum pump, and hemofilter.
The research team said that the technology can be used to load erythrocytes with peptides or nucleic acids as well as chemical compounds. In some cases, the procedure seems to work best if the drug is phosphorylated before encapsulation. Enzymatic reactions in the red blood cells remove the phosphate group from the drug, which then leaks through cell pores and freely enters the bloodstream.
In laboratory tests, the research team found that red blood cells could be loaded with a ubiquitin analog and modified to promote uptake by macrophages. Through normal lysis of the red blood cells, the peptide was released into the macrophages, where it inhibited activation of NF-kB, a transcription factor that may play an important role in the onset of inflammation.
The researchers also speculated that red blood cells could be used to encapsulate and deliver genes, creating a possible alternative to viral-based gene delivery systems.