The Effect of Encapsulation in Red Blood Cells on the Distribution of Methotrexate in Mice

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Abstract
Red blood cell ghosts containing entrapped methotrexate were injected into mice. The distribution pattern of the antitumor drug among different organs was markedly different from that observed after injection of free methotrexate. Methotrexate is trapped inside mouse and human red blood cell ghosts by application of an electric field pulse of 8 and 12 kV/cm, respectively, for 40 .mu.s through an isotonic red blood cell suspension containing 5 mmol/l methotrexate between 0-4.degree. C. The electrical field induces a permeability change of the cell membrane, which results from the dielectric breakdown of the cell membrane, leading to an exchange of ions and macromolecules between the cell interior and the external medium containing the drug. After resealing by raising the temperature to 37.degree. C, the cells contained about 5 mmol/l methotrexate. The methotrexate-loaded ghost population, obtained from mouse or human red blood cells, was electrically homogeneous as shown by dielectric breakdown measurements using a hydrodynamic focusing Coulter counter. Twenty-five micrograms methotrexate labeled with 22 kBq [3'',5'',9(n)-3H]methotrexate (specific activity 0.63 TBq/mmol) trapped inside human or mouse ghost cells was injected into the tail vein of mice (about 20 g body wt). Nearly all of the entrapped methotrexate accumulated in the liver, whereas in control experiments only 0.25 of the injected dose accumulated in the liver. This carrier system can be made specific for other organs by entrapping, in addition to the drug, small para-, ferro- or ferrimagnetic particles of 4-20 nm in diameter, and using an external magnetic guide.

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