When placed in a hypotonic solurion, human erythrocytes have a remarkable capacity to undergo reversible membrane swelling with a concomitant appearance of pores large enough to be crossed by metabolites, macromolecules and drugs. This property has been carefully investigated and resealed erythrocytes have been recently proposed as extraordinary vehicles for the dissemination of drugs in ciurculation. Moreover, drug-loaded erythrocytes can be modified to increase their recognition and phagocytosis by human macrophages (1). Monocyte-derived macrophages play a central role in the pathogenesis of infection by immunodeficiency virus (HIV-1) and represent the main reservoir of the virus for HIV. In addition macrophages can also be easily infected by various herpesviruses, including herpes virus type 1 (HSV-1). As for HIV, macrophages can become a natural reservoir of latent HSV-1; hence, therapeutic strategies able to inhibit replication of both viruses in macrophages are needed. Based on previous results (2) ad known the efficacy of PMEA and PMPA against HIV replication and that of ACV and PMEA against HSV replication, new nucleotide analogues with both anti-HIV and anti-HSV activity, were designed and synthesized. By a procedure of hypotonic resealing and rennealing, the homodinucleotide (Bis-PMEA) or the heterodinucleotide (ACVpPMPA) was encapsulated into erythrocytes and targeted selectively to human macrophages. Once inside macrophages, drug degradation occurred to yield the pharmacologically active metabolites. The addition of Bis-PMEA or ACVpPMPA-loaded erythrocytes to human macrophages provided effective in vitro protection from both HIV-1 and HSV-1 replications. 1. Magnani m et al (1996) Proc. Natl. Acad. Sci. USA 93, 4403-08 2. Rossi l et al (1998) AIDS Res Hum. Retrov. 14(5): 435-444
Red Blood cells as drug delivery system for antiviral nucleotide analogues
CAPPELLACCI, Loredana;FRANCHETTI, Palmarisa
1999-01-01
Abstract
When placed in a hypotonic solurion, human erythrocytes have a remarkable capacity to undergo reversible membrane swelling with a concomitant appearance of pores large enough to be crossed by metabolites, macromolecules and drugs. This property has been carefully investigated and resealed erythrocytes have been recently proposed as extraordinary vehicles for the dissemination of drugs in ciurculation. Moreover, drug-loaded erythrocytes can be modified to increase their recognition and phagocytosis by human macrophages (1). Monocyte-derived macrophages play a central role in the pathogenesis of infection by immunodeficiency virus (HIV-1) and represent the main reservoir of the virus for HIV. In addition macrophages can also be easily infected by various herpesviruses, including herpes virus type 1 (HSV-1). As for HIV, macrophages can become a natural reservoir of latent HSV-1; hence, therapeutic strategies able to inhibit replication of both viruses in macrophages are needed. Based on previous results (2) ad known the efficacy of PMEA and PMPA against HIV replication and that of ACV and PMEA against HSV replication, new nucleotide analogues with both anti-HIV and anti-HSV activity, were designed and synthesized. By a procedure of hypotonic resealing and rennealing, the homodinucleotide (Bis-PMEA) or the heterodinucleotide (ACVpPMPA) was encapsulated into erythrocytes and targeted selectively to human macrophages. Once inside macrophages, drug degradation occurred to yield the pharmacologically active metabolites. The addition of Bis-PMEA or ACVpPMPA-loaded erythrocytes to human macrophages provided effective in vitro protection from both HIV-1 and HSV-1 replications. 1. Magnani m et al (1996) Proc. Natl. Acad. Sci. USA 93, 4403-08 2. Rossi l et al (1998) AIDS Res Hum. Retrov. 14(5): 435-444I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
