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).
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.
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|Guijas, Carlos; Montenegro-Burke, J Rafael; Warth, Benedikt et al. (2018) Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat Biotechnol 36:316-320|
|Beyer, Brittney A; Fang, Mingliang; Sadrian, Benjamin et al. (2018) Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nat Chem Biol 14:22-28|
|Herskovitz, Jonathan; Gendelman, Howard E (2018) HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication. J Neuroimmune Pharmacol :|
|Kevadiya, Bhavesh D; Woldstad, Christopher; Ottemann, Brendan M et al. (2018) Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution. Theranostics 8:256-276|
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