Infusion of red blood cell-loaded asparaginase in monkey. Immunologic, metabolic, and toxicologic consequences.

Abstract

In order to evaluate enzyme loading of RBCs as a drug delivery system, the antitumor agent asparaginase was loaded into the erythrocytes of nine monkeys at three different doses and autologously injected back into these animals. Nine control monkeys were also once injected intravenously at the same doses of enzyme, but the enzyme was free in solution rather than entrapped in RBCs. The RBCs and asparaginase were labeled with 51Cr and 125I, respectively. The circulating half-life of the enzyme-loaded, resealed RBCs was 7 days, as compared to 9 days in the control RBCs. Beginning at 5 days, circulating enzyme activity was several orders of magnitude higher in the monkeys injected with RBC-loaded asparaginase than in controls. Targeting of drug-loaded RBCs into the spleen and liver was apparent. Suppression of the serum substrate level of asparaginase in the monkeys treated with the single intravenous injection of RBCs loaded with asparaginase was 20 days, which was twice as long as the suppression in the control monkeys. Production of anti-asparaginase antibody was shown to reach a higher level and persist longer in the monkeys with RBC-entrapped asparaginase. Evidence was also obtained showing that entrapping asparaginase in RBCs protects against anaphylaxis in the guinea pig. Thus this drug delivery system is also proposed as a strategy to avoid life-threatening allergic reactions. Advantages and limitations of RBC loading as a drug delivery system are discussed.