Encapsulation of adriamycin in human erythrocytes.
Adriamycin (doxorubicin) was encapsulated in human erythrocytes by means of a dialysis technique involving transient hypotonic hemolysis followed by isotonic resealing. Up to 1.6 mg of the drug was entrapped per ml of packed erythrocytes, with the efficiency of encapsulation being 60-80%. In vitro incubation of the Adriamycin-loaded erythrocytes in autologous plasma was accompanied by progressive release of unaltered Adriamycin in the medium. The efflux was still evident after 50 hr. The metabolism of encapsulated Adriamycin was restricted to limited formation of the C-13 hydroxylated metabolite, adriamycinol, in the normal erythrocytes but not in erythrocytes from individuals deficient in glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP+ 1-oxidoreductase, EC 1.1.1.49) activity. Reductive bioactivation of encapsulated Adriamycin to yield the corresponding aglycones was not observed in a variety of conditions. However, when NADPH ferredoxin reductase and ferredoxin, both purified from spinach leaves, were co-entrapped within erythrocytes and allowed to catalyze electron transfer to Adriamycin intracellularly under N2, a quantitative conversion to 7-deoxyadriamycin aglycone was obtained. Adriamycin-loaded erythrocytes did not show any significant oxidative damage, except for a variable increase of methemoglobin, suggesting some redox cycling between native Adriamycin and its semiquinone radical. Encapsulation of Adriamycin in autologous human erythrocytes may represent a therapeutic strategy for the slow release in circulation of this antineoplastic drug in order to reduce or prevent its adverse effects and especially the delayed cardiotoxicity that limits its use in patients with neoplastic disease.
De Flora
A
A
Benatti
U
U
Guida
L
L
Zocchi
E
E
D001711:Biotransformation; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000378:metabolism; D006801:Humans; D008297:Male; D008706:Methemoglobin / Q000096:biosynthesis
D004317:Doxorubicin; D008706:Methemoglobin