Heterodimer-loaded erythrocytes as bioreactors for slow delivery of the antiviral drug azidothymidine and the antimycobacterial drug ethambutol

Disseminated infection,vith Mycobacterium avium complex (MAC) remains the m ost common serious bacterial infection in patients with advanced AIDS. The organisms that make up this complex are found ubiquitously in the environme nt, yet rarely cause disseminated disease in nonimmunocompromised human pat ients; on the contrary, up to 50% of patients with AIDS may ultimately deve lop the pathology, Hence, therapeutic strategies able to inhibit HIV and My cobacterium replication are needed. Because of the rapid plasma elimination and toxicity of the most commonly used drugs, daily multiple-drug therapie s must often be continued throughout life, frequently causing major side ef fects and, as a consequence, poor patient compliance. Therefore, alternativ e strategies that reduce the toxicity of the drugs and allow prolonged appl ication intervals are sorely needed. Since erythrocytes (RBCs) can behave a s bioreactors able to convert impermeant prodrugs to membrane-releasable ac tive drugs, new compounds (AZTpEMB, AZTpEMBpAZT, and AZTp(2)EMB) consisting of both an antiretroviral and an antimicrobial drug were designed and synt hesized. Among these, only AZTp2EMB was hydrolyzed by erythrocyte enzymes a nd could be encapsulated inside RBCs, AZTp(2)EMB-loaded RBCs slowly release d AZT and EMB in culture medium, reducing its concentration by one-half abo ut every 48 hr of incubation at 37 degrees C, Moreover, when AZTp(2)EMB-loa ded erythrocytes were incubated for 6 days in the presence of human macroph ages infected with Mycobacterium avium (M. avium) a marked bactericidal eff ect (>1 log) was observed. Thus, AZTp(2)EMB-loaded erythrocytes could be us ed as endogenous bioreactors for AZT and EMB delivery in the treatment of H IV and M, avium infection.