The optimal physical and chemical requirements for synthesis of nanoformulated antiretroviral drugs nanoART) into phospholipid coated nanoparticles and block copolymer micelles will be developed. Manufacture will be performed to facilitate cell uptake and slow release and pharmacokinetic (PK) studies (Project 2, H. Gendelman) and for PK and antiretroviral studies as performed in infected animals (Project 3, H. Fox). Although integration between formulation synthesis;in vitro testing for cytotoxicity, nanoparticle encased drug uptake and release;and in vivo rodent PK has been achieved, optimization of synthesis for inevitable clinical use will require continued integration and works. We posit that this will be realized with none or limited cell and tissue toxicities. A principal focus for this project is to consistently achieve high consistent antiretroviral drug levels in virus-target tissues including the lymphoid and central nervous systems. To address this, the project seeks a robust and scalable procedure for preparation of nanoART formulations with optimal size range, surface coating and colloidal stability. This would maximize circulating monocyte uptake and delivery to sites of active viral growth. Five drugs are proposed that include efavirenz, ritonavir, indinavir, lopinavir and atazanavir of which three will be used in large animal tests. The precipitation, homogenization, wet milling and micelle solubilization techniques will be used to prepare nanoART with adequate stability, both chemical and physical, for sufficient drug loading, appropriate osmolarity, viscosity and sterility. This will be performed in full compliance with United States Pharmacopeia practices. The """"""""best"""""""" nanoART formulations, determined by bioimaging (Core B, M. Boska) and appropriate PK support (Core C, C. Fletcher) will be scaled-up for animal testing using Core A, H. Gendelman as a development and logistical guide. The strengths of this project rest in multiple areas including the now extensive """"""""new"""""""" preliminary data, the expertise of the investigators, the research environment, and the clear cooperation and integration made between the cores and the projects. Excitement surrounds the integration of multiple scientific approaches to derive clinical benefit in a set need for substance abusers.
The development of an efficient process to manufacture nanosuspensions of pooriy water-soluble antiretroviral therapies (ART) with high levels of drug loading will improve bioavailability of drugs to combat HIV/AIDS. Success will lay the foundation for subsequent bench to bedside research towards pioneering long acting injectable ART for noncompliant patients.
| Montenegro-Burke, J Rafael; Woldstad, Christopher J; Fang, Mingliang et al. (2018) Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress. Mol Neurobiol : |
| Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410 |
| Schutt, Charles R; Gendelman, Howard E; Mosley, R Lee (2018) Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson's disease. Mol Neurodegener 13:26 |
| Sillman, Brady; Bade, Aditya N; Dash, Prasanta K et al. (2018) Creation of a long-acting nanoformulated dolutegravir. Nat Commun 9:443 |
| Forsberg, Erica M; Huan, Tao; Rinehart, Duane et al. (2018) Data processing, multi-omic pathway mapping, and metabolite activity analysis using XCMS Online. Nat Protoc 13:633-651 |
| Thomas, Midhun B; Gnanadhas, Divya Prakash; Dash, Prasanta K et al. (2018) Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond) 13:2139-2154 |
| Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) URMC-099 facilitates amyloid-? clearance in a murine model of Alzheimer's disease. J Neuroinflammation 15:137 |
| 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 : |
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