TY - JOUR
T1 - Inhibition of HIV-1 replication in macrophages by a heterodinucleotide of lamivudine and tenofovir
AU - Rossi, Luigia
AU - Franchetti, Palmarisa
AU - Pierigé, Francesca
AU - Cappellacci, Loredana
AU - Serafini, Sonja
AU - Balestra, Emanuela
AU - Perno, Carlo Federico
AU - Grifantini, Mario
AU - Caliò, Raffaele
AU - Magnani, Mauro
PY - 2007/4
Y1 - 2007/4
N2 - Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine and tenofovir which have been shown to act synergistically and (ii) to protect macrophages from 'de novo' HIV-1-infection through its administration. Methods: 3TCpPMPA was obtained by coupling the morpholidate derivative of tenofovir with the mono n-tri-butylammonium salt of lamivudine 5′-monophosphate. Stability and metabolism were evaluated in vitro and in vivo in mice. 3TCpPMPA was encapsulated into autologous erythrocytes by a procedure of hypotonic dialysis, isotonic resealing and reannealing. 3TCpPMPA-loaded erythrocytes were modified to increase their phagocytosis by human macrophages. Macrophages were infected by HIV-1Ba-L and inhibition of HIV-1 replication was assessed by HIV p24gag quantification. Results: Pharmacokinetic studies in mice revealed a rapid disappearance of the heterodinucleotide from circulation (t1/2 = 15 min) without any advantage compared with the administration of single drugs. Adding free 3TCpPMPA to macrophages (18 h), a 90% inhibition of viral replication up to 35 days post-treatment was achieved, while only a 60% inhibition was obtained by the combined treatment 3TC and (R)PMPA. When 3TCpPMPA was selectively targeted to the macrophage compartment by a single addition of loaded erythrocytes, the protection of macrophages from 'de novo' infection (99% protection 3 weeks post-treatment) was nearly complete. Conclusions: Erythrocytes loaded with 3TCpPMPA and modified to increase their phagocytosis are able to protect macrophages from 'de novo' HIV-1 infection. 3TCpPMPA acts as an efficient antiviral pro-drug that, once inside macrophages, can be slowly converted into 3TCMP and (R)PMPA protecting these cells for a longer period of time.
AB - Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine and tenofovir which have been shown to act synergistically and (ii) to protect macrophages from 'de novo' HIV-1-infection through its administration. Methods: 3TCpPMPA was obtained by coupling the morpholidate derivative of tenofovir with the mono n-tri-butylammonium salt of lamivudine 5′-monophosphate. Stability and metabolism were evaluated in vitro and in vivo in mice. 3TCpPMPA was encapsulated into autologous erythrocytes by a procedure of hypotonic dialysis, isotonic resealing and reannealing. 3TCpPMPA-loaded erythrocytes were modified to increase their phagocytosis by human macrophages. Macrophages were infected by HIV-1Ba-L and inhibition of HIV-1 replication was assessed by HIV p24gag quantification. Results: Pharmacokinetic studies in mice revealed a rapid disappearance of the heterodinucleotide from circulation (t1/2 = 15 min) without any advantage compared with the administration of single drugs. Adding free 3TCpPMPA to macrophages (18 h), a 90% inhibition of viral replication up to 35 days post-treatment was achieved, while only a 60% inhibition was obtained by the combined treatment 3TC and (R)PMPA. When 3TCpPMPA was selectively targeted to the macrophage compartment by a single addition of loaded erythrocytes, the protection of macrophages from 'de novo' infection (99% protection 3 weeks post-treatment) was nearly complete. Conclusions: Erythrocytes loaded with 3TCpPMPA and modified to increase their phagocytosis are able to protect macrophages from 'de novo' HIV-1 infection. 3TCpPMPA acts as an efficient antiviral pro-drug that, once inside macrophages, can be slowly converted into 3TCMP and (R)PMPA protecting these cells for a longer period of time.
KW - Drug-delivery
KW - HIV/AIDS
KW - Nucleoside analogues
KW - Phagocytes
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U2 - 10.1093/jac/dkm011
DO - 10.1093/jac/dkm011
M3 - Article
C2 - 17327293
AN - SCOPUS:34250027994
VL - 59
SP - 666
EP - 675
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 4
ER -