  High throughput screening of small molecules and natural products is costly,
requiring significant amounts of time, reagents, and operating space. Although
microarrays have proven effective in the miniaturization of screening for
certain biochemical assays, such as nucleic acid hybridization or antibody
binding, they are not widely used for drug discovery in cell culture due to the
need for cells to internalize lipophilic drug candidates. Lipid droplet
microarrays are a promising solution to this problem as they are capable of
delivering lipophilic drugs to cells at dosages comparable to solution
delivery. However, the scalablility of the array fabrication, assay validation,
and screening steps has limited the utility of this approach. Here we
demonstrate a scalable process for lipid droplet array fabrication, assay
validation in cell culture, and drug screening. A nanointaglio printing process
has been adapted for use with a printing press. The arrays are stabilized for
immersion into aqueous solution using a vapor coating process. In addition to
delivery of lipophilic compounds, we found that we are also able to encapsulate
and deliver a water-soluble compound in this way. The arrays can be
functionalized by extracellular matrix proteins such as collagen prior to cell
culture as the mechanism for uptake is based on direct contact with the lipid
delivery vehicles rather than diffusion of the drug out of the microarray
spots. We demonstrate this method for delivery to 3 different cell types and
the screening of 90 natural product extracts on a microarray covering an area
of less than 0.1 cm2. The arrays are suitable for miniaturized screening, for
instance in BSL-3 conditions where space is limited and for applications where
cell numbers are limited, such as in functional precision medicine.
