title: A nanoparticle-encapsulated non-nucleoside reverse-transcriptase inhibitor with enhanced anti-HIV-1 activity and prolonged circulation time in plasma.
abstract: Non-nucleoside reverse-transcriptase inhibitors (NNRTIs), major components of highly active antiretroviral therapy (HAART), are effective in suppressing viral replication and preventing the progress of HIV-1 infection to AIDS. However, rapid blood clearance in vivo could significantly impair the efficiency of the anti-HIV-1 activity and result in multiple daily doses which might lead to poor patient compliance. Here we attempted to employ biodegradable organic nanoparticles (NPs) to encapsulate DAAN15h, a derivative of 4-substituted 1, 5-diarylaniline with potent anti-HIV activities. Nanoparticles encapsulating DAAN15h (NP-DAAN15h) displayed a spherical shape with a size of 97.01 ± 3.64 nm and zeta potential of -19.1 ± 3.78 mV, and they exhibited a sustained controlled release behavior in vitro. The cellular uptake of NPs on TZM-b1 cells, MT-2 cells and M7 cells, possibly through lipid raft-mediated and energydependent active transport processes, was significantly enhanced. NP-DAAN15h, which possessed no significant in vitro cytotoxicity, showed improved antiviral activity against laboratory-adapted and primary HIV-1 isolates with different subtypes and tropisms, including RT-resistant variants. NP-DAAN15h exhibited a significantly prolonged blood circulation time, decreased plasma elimination rate, and enhanced AUC(0-t). NP-DAAN15h, a nanoparticle-encapsulated NNRTI, exhibits enhanced cellular uptake, improved anti-HIV-1 efficacy and prolonged in vivo circulation time, suggesting good potential for further development as a new NNRTI formulation for clinical use.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Bingjie
authors.initials: B
authors.lastname: Qin
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Shanghai Medical College and Institute of Medical Microbiology, Fudan University, 130 Dong An Road, Rm 611, Shanghai 200032, China. shibojiang@fudan.edu.cn.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001776:Blood Circulation Time / Q000379:methods; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000097:blood*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D004337:Drug Carriers; D018894:Reverse Transcriptase Inhibitors