Sustained-release nanoART formulation for the treatment of neuroAIDS

Rahul Dev Jayant, Venkata SR Atluri, Marisela Agudelo, Vidya Sagar, Ajeet Kaushik, Madhavan Nair Center for Personalized Nanomedicine, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA Abstract: A novel approach was developed for the coencapsulation of an anti-HIV drug (tenofovir) and a latency-breaking agent (vorinostat), using magnetically guided layer-by-layer (LbL) assembled nanocarriers for the treatment of neuroAIDS. Ultrasmall iron oxide (Fe3O4) nanoparticles (10±3 nm) were synthesized and characterized. The LbL technique was used to achieve a sustained release profile, and application of 2 bilayers ([tenofovir+dextran sulphate]2+vorinostat) to magnetic nanoparticles resulted in a 2.8 times increase in drug (tenofovir) loading and also resulted in an increase in the drug release period by 30-fold, with 100% drug release in sustained manner over a period of 5 days with the simultaneous stimulation of latent HIV expression. Nanoformulation showed a good blood–brain barrier transmigration ability (37.95%±1.5%) with good in vitro antiviral efficacy (~33% reduction of p24 level) over a period of 5 days after HIV infection in primary human astrocytes, with good cell viability (>90%). Hence, LbL arrangements of drugs on magnetic nanoparticles provides sustained release and, therefore, may improve the patient’s adherence to therapy and lead to better compliance. Keywords: layer-by-layer, magnetic nanocarriers, blood–brain barriers, neuroAIDS, sustained release, anti-HIV drug, latenc

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Venkata Subba Rao Atluri* Rahul Dev Jayant* Sudheesh Pilakka-Kanthikeel, Gabriella Garcia, Thangavel Samikkannu, Adriana Yndart, Ajeet Kaushik, Madhavan Nair Center for Personalized Nanomedicine, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA *These authors contributed equally to this work Abstract: Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood–brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients. Keywords: HIV, neurocognitive disorders, TIMP1, magnetic nanoparticles, blood–brain barrier, neuroprotectio

In Vitro Models of Central Nervous System Barriers for Blood-Brain Barrier Permeation Studies

One of the biggest challenging diseases are the neurodegenerative diseases which are not easy to target due to the presence of a complex semipermeable, dynamic, and adaptable barrier between the central nervous system (CNS) and the systemic circulation termed as the blood-brain barrier (BBB), which controls the exchange of molecules. Its semipermeable nature restricts the movement of bigger molecules, like drugs, across it and leads to minimal bioavailability of drugs in the CNS. This poses the biggest shortcoming in the development of therapeutics for CNS disorders. Although the complexity of the BBB muddles the drug delivery approaches into the CNS and can promote disease progression, understanding the composition and functions of BBB provides a platform for unraveling the way toward drug development. The BBB is comprised of brain microvascular endothelial CNS cells which communicate with other CNS cells (astrocytes, pericytes) and behave according to the state of the CNS, by retorting against pathological environments and modulating disease progression. This chapter discusses the fundamentals of BBB, permeation mechanisms, an overview of different in vitro BBB models with their advantages and disadvantages, and rationale of selecting penetration prediction methods toward the important role in the development of CNS therapeutics