Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain

Abstract

Antiviral therapy using nucleoside reverse transcriptase inhibitors (NRTIs) is neurotoxic and has low efficiency in eradication of HIV-1 harbored in central nervous system (CNS). Previously, we reported that active 5′-triphosphates of NRTIs encapsulated in cationic nanogels (nano-NRTIs) suppress HIV-1 activity more efficiently than NRTIs and exhibit reduced mitochondrial toxicity1,2. Here, we demonstrated low neurotoxicity and excellent antiviral activity of nano-NRTIs decorated with the peptide (AP) binding brain-specific apolipoprotein E receptor. Nano-NRTIs induced lower levels of apoptosis and formation of reactive oxygen species, a major cause of neuron death, than free NRTIs. Optimization of size, surface decoration with AP significantly increased brain accumulation of nano-NRTIs. The efficient CNS delivery of nano-NRTIs resulted in up to 10-fold suppression of retroviral activity and reduced virus-associated inflammation in humanized mouse model of HIV-1 infection in the brain. Our data provide proof of the advanced efficacy of nano-NRTIs as safer alternative of current antiviral drugs.

Nanoparticles for Brain-Specific Drug and Genetic Material delivery, Imaging and Diagnosis

“…In vivo administration of nanogel-nucleoside reverse transcriptase inhibitors decorated with a peptide binding brain-specific apolipoprotein E receptor resulted in increased brain accumulation, and high retroviral activity in a humanized mouse model of HIV-1 infection in the brain [41]. In addition, PEI copolymers have been also used to transfect stem cells, an example of this being retinoic acid-PEI complex nanoparticles inducing embryonic stem cell-derived neuronal differentiation [42].…”

Infectious Diseases: Need for Targeted Drug Delivery

“…Further, in vivo administration of anti-CCR5 siRNA resulted in leukocytespecifi c gene silencing that was sustained for 10 days [ 248 ]. Nanogels comprising non-reverse transcriptase inhibitors (NRITs) decorated with a peptide for brain specifi c apolipoprotein E (apoE) receptors, showed tenfold suppression of retroviral activity and decrease infl ammation in humanised mouse model of HIV-1 infection in the brain [ 249 ].…”

Amphiphilic Cationic Nanogels as Brain-Targeted Carriers for Activated Nucleoside Reverse Transcriptase Inhibitors

“…In recent years, various approaches to deliver drugs into the CNS using different receptors on the BBB endothelium demonstrated their practical potential (Tiwari and Amiji 2006; Zensi et al 2009). Peptide molecules showed a special promise for targeted brain delivery via systemic drug administration (Delehanty et al 2010; Li et al 2011; Gerson et al 2014). In the CNS, HIV-1 resides mostly in microglia or macrophages, however, other brain-associated cells may become infected with HIV-1 in vivo with variable levels of HIV-1 mRNA expression.…”

“…The diverse cellular reservoirs for HIV-1 in the CNS may be critically linked to the molecular mechanisms involved in HIV-1 neuropathogenesis, for example, in vivo infection of the BBB endothelial cells, and possibly cells in the choroid plexus, may directly contribute to penetration of the BBB by HIV-1 (Bagasra et al 1996). Recently, we demonstrated the strong potential of LDL receptor-specific ApoE peptide-modified NG/NTP for the treatment of HIV-1 infection in the CNS using a humanized HIV mouse model (Gerson et al 2014). In this approach, 10-fold reduction in RT activity in the brain was achieved by accumulation of therapeutic levels of nanogel-formulated Zidovudine 5’-triphosphate (ZTP) after systemic administration.…”