P-D8 Macrophage exosomes as novel antiretroviral drug delivery platforms

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Exosomes are 30–150 nm extracellular vesicles that transport RNAs, proteins and small molecules between cells. Exosomes serve as endogenous carriers of biological cargo with natural features for immune cell targeting, and thus have generated immense interest for drug delivery. Herein we tested 2 methods of drug loading into exosomes. First, we dosed human monocyte-derived macrophages (MDM) with native and nanoformulated atazanavir (nanoATV) and assessed drug loading into released exosomes. MDM showed avid abilities to produce drug-loaded nanoparticles over a period of 14 days. MDM dosed with native ATV secreted ∼1.5 μg of ATV/109 exosomes whereas 500 ng of ATV/109 exosomes were secreted with nanoATV at day 1 and 3. At day 7 nanoATV treated MDM secreted ∼1 μg of ATV in /109 exosomes while for native ATV loaded MDM drug levels were at or below limits of detection. The drug concentration was increased 1.5 fold when MDM were treated with URMC-099, a mixed lineage kinase inhibitor known to potentiate macrophage nanoparticle sequestration. Second, drug loading into naïve exosomes ex vitro was investigated. Three methods of ATV incorporation were employed: sonication, freeze-thaw and incubation with 0.2% saponin. The freeze-thaw method resulted in the lowest drug loading, 11.3 μg/mL of exosomes. Incubation with saponin at RT increased loading to 19.2 μg/mL. Sonication allowed for the greatest drug loading, 57.9 μg/mL Together we posit that exosomes can be harnessed as carriers for antiretroviral drugs with natural targeting machineries for macrophage delivery. As exosomes are known to cross blood brain barrier and known to reach lymphoid organs, this delivery system could be used to target HIV reservoirs.

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