Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection.

Nucleoside reverse transcriptase inhibitors (NRTIs) are an integral part of the current antiretroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-ε-polylysine (CEPL) nanogels by conjugation with NRTI 5'-succinate derivatives (sNRTI). Biodegradability, small particle size, and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2-10, 2-4, and 1-2 µM drug levels, respectively, for single nanodrugs and dual and triple nanodrug cocktails. Nanogel conjugate of lamivudine was the most effective single nanodrug (EC90 2 µM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Infrequent iv injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.