The foundation of this project now rests on its abilities to bridge formulation synthesis to testing for clinical efficacy in virus-infected animals. In support of this notion, we have now achieved a linkage between the most efficient formulations for in vitro testing with pharmacokinetic (PK) testing. This serves to significantly strengthen the notion put forward in the prior submission but strengthened in the current re-submission that an injectable form of nanoformulated antiretrovirals can be achieved for future clinical use. Nonetheless we acknowledge that significant research in development still needs to be performed to see this goal as a definable reality. In this regard, nanoformulated antiretroviral therapies [nanoART;indinavir (IDV), lopinavir (LPV), efavirenz (EFV), atazanavir (ATZ) and ritonavir (RTV)] will be investigated for cell uptake, release, and PK responses in human laboratory cell culture systems and in rodents. To date three (IDV, RTV, and EFV), in preliminary experiments, have demonstrated robust uptake in monocyte-derived macrophages and drug release, measured in weeks, beyond an established plasma effective concentrationso (EC50). We posit that size, composition, coating, and charge can enhance nanoART uptake into monocytes and monocytederived macrophages and subsequent drug delivery into viral reservoirs. This includes the lymphoreticular and the central nervous systems. This project aims to test efficiency of cell-based nanoART and to explore relevant toxicities in laboratory cell systems and mice in support of antiretroviral efficacy tests in small (rodent) and large animals (rhesus macaques) (H. Fox, project 3). The project is highly interactive with project 1 (A. Kabanov) and cores A, B, and C (H. Gendelman, M. Boska and C. Fletcher).

Public Health Relevance

Laboratory and rodent pharmacokinetic studies will be done in rodents to provide proof of concept for the use of long acting nanoformulated antiretroviral medicines for large animal and inevitable future clinical use Translation of these findings will be made through efficacy studies in infected animal studies and guided through the scientific interactions established in this project and projects 1 and 3.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA028555-03
Application #
8378248
Study Section
Special Emphasis Panel (ZRG1-AARR-D)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$313,975
Indirect Cost
$102,545
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Stauch, Kelly L; Emanuel, Katy; Lamberty, Benjamin G et al. (2017) Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals. J Neurovirol 23:795-807
Heinrichs-Graham, Elizabeth; Santamaria, Pamela M; Gendelman, Howard E et al. (2017) The cortical signature of symptom laterality in Parkinson's disease. Neuroimage Clin 14:433-440
Kevadiya, Bhavesh D; Bade, Aditya N; Woldstad, Christopher et al. (2017) Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging. Acta Biomater 49:507-520
Araínga, Mariluz; Edagwa, Benson; Mosley, R Lee et al. (2017) A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy. Retrovirology 14:17
Gnanadhas, Divya Prakash; Dash, Prasanta K; Sillman, Brady et al. (2017) Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest 127:857-873
Shahnaz, Gul; Edagwa, Benson J; McMillan, JoEllyn et al. (2017) Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis. Nanomedicine (Lond) 12:99-115
Gendelman, Howard E (2017) Thank You! J Neuroimmune Pharmacol 12:565
Embury, Christine M; Dyavarshetty, Bhagyalaxmi; Lu, Yaman et al. (2017) Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease. J Neuroimmune Pharmacol 12:340-352
Bade, Aditya N; Gendelman, Howard E; Boska, Michael D et al. (2017) MEMRI is a biomarker defining nicotine-specific neuronal responses in subregions of the rodent brain. Am J Transl Res 9:601-610
Edagwa, Benson; McMillan, JoEllyn; Sillman, Brady et al. (2017) Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv 14:1281-1291

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