The goals of the Therapeutics core are to provide nanoformulations to invesfigators pursuing nanoformulated ntiretroviral and neuroprotective therapies for increased central nervous system (CNS) penetrance. The formulations developed address how monocytes and other immune cells may be harnessed for drug delivery. Before such novel therapies can be administered to people, we will determine, in well-validated laboratory and animal models, the optimal doses and formulation administration. The crux of the problem facing the Core, namely can nanoformulated antiretroviral therapy show sustained antiretroviral responses and slow release of drug in tissues, has now been addressed. The Core addresses a specific and important issue in the treatment of HIV and neuroAIDS, with broader implications for therapeutic interventions to other neurodegenerative diseases. Through this project, we will identify and manufacture candidate Nanoformulations of currently used efficacious antiretrovirals. These will be tested model systems of human disease, ranging from cultured monocytes to mice to monkeys, to examine pharmacokinefic, safety and efficacy. This Core, overall, represents work that may prove to be a major advance in the development of long-lasting therapeutic agents that can lead to real treatments both systemic and CNS human disease.

Public Health Relevance

The manufacture of nanosuspensions of poorly water-soluble antiretroviral drugs with high levels of drug loading will improve bioavailability to combat HIV/AIDS in hidden viral sanctuaries including the nervous system. Success will lay the foundation for a broad range of bench to bedside research towards pioneering long acting injectable drugs for CNS drug delivery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Center Core Grants (P30)
Project #
5P30MH062261-14
Application #
8629789
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$176,883
Indirect Cost
$57,769
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Dave, Rajnish S; Jain, Pooja; Byrareddy, Siddappa N (2018) Functional Meningeal Lymphatics and Cerebrospinal Fluid Outflow. J Neuroimmune Pharmacol 13:123-125
Dyavar, Shetty Ravi; Ye, Zhen; Byrareddy, Siddappa N et al. (2018) Normalization of cell associated antiretroviral drug concentrations with a novel RPP30 droplet digital PCR assay. Sci Rep 8:3626
Ottemann, Brendan M; Helmink, Austin J; Zhang, Wenting et al. (2018) Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. Biomaterials 185:174-193
Brenza, Timothy M; Schlichtmann, Benjamin W; Bhargavan, Biju et al. (2018) Biodegradable polyanhydride-based nanomedicines for blood to brain drug delivery. J Biomed Mater Res A 106:2881-2890
Sathyanesan, Monica; Watt, Michael J; Haiar, Jacob M et al. (2018) Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus. Transl Psychiatry 8:113
Zhou, Tian; Su, Hang; Dash, Prasanta et al. (2018) Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 151:53-65
Thangaraj, Annadurai; Periyasamy, Palsamy; Liao, Ke et al. (2018) HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy. Autophagy 14:1596-1619
Kevadiya, Bhavesh D; Ottemann, Brendan M; Thomas, Midhun Ben et al. (2018) Neurotheranostics as personalized medicines. Adv Drug Deliv Rev :
Wiesman, Alex I; O'Neill, Jennifer; Mills, Mackenzie S et al. (2018) Aberrant occipital dynamics differentiate HIV-infected patients with and without cognitive impairment. Brain 141:1678-1690
Periyasamy, Palsamy; Thangaraj, Annadurai; Guo, Ming-Lei et al. (2018) Epigenetic Promoter DNA Methylation of miR-124 Promotes HIV-1 Tat-Mediated Microglial Activation via MECP2-STAT3 Axis. J Neurosci 38:5367-5383

Showing the most recent 10 out of 374 publications