Sustained and specific in vitro inhibition of HIV-1 replication by a protease inhibitor encapsulated in gp120-targeted liposomes.
Selective delivery of antiretrovirals to human immunodeficiency virus (HIV) infected cells may reduce toxicities associated with long-term highly active antiretroviral therapy (HAART), may improve therapeutic compliance and delay the emergence of resistance. We developed sterically stabilized pegylated liposomes coated with targeting ligands derived from the Fab' fragment of HIV-gp120-directed monoclonal antibody F105, and evaluated these liposomes as vehicles for targeted delivery of a novel HIV-1 protease inhibitor. We demonstrated that the immunoliposomes were selectively taken up by HIV-1-infected cells and localized intracellularly, enabling the establishment of a cytoplasmic reservoir of protease inhibitor. In antiviral experiments, the drug delivered by the immunoliposomes showed greater and longer antiviral activity than comparable concentrations of free drug or drug encapsulated in non-targeted liposomes. In conclusion, by combining a targeting moiety with drug-loaded liposomes, efficient and specific uptake by non-phagocytic HIV-infected cells was facilitated, resulting in drug delivery to infected cells. This approach to targeted delivery of antiretroviral compounds may enable the design of drug regimens for patients that allow increased therapeutic adherence and less toxic treatment of HIV infection.
Clayton
Reginald
R
Tibotec BVBA, Generaal De Wittelaan L 11B 3, Mechelen, Belgium. rclayton@its.jnj.com
Ohagen
Asa
A
Nicol
Francois
F
Del Vecchio
Alfred M
AM
Jonckers
Tim H M
TH
Goethals
Olivia
O
Van Loock
Marnix
M
Michiels
Lieve
L
Grigsby
John
J
Xu
Zheng
Z
Zhang
Yuan Peng
YP
Gutshall
Lester L
LL
Cunningham
Mark
M
Jiang
Haiyan
H
Bola
Sharon
S
Sarisky
Robert T
RT
Hertogs
Kurt
K
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004337:Drug Carriers / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D004337:Drug Carriers; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; D008081:Liposomes; D011092:Polyethylene Glycols