Lipidoid nanoparticles increase ATP uptake into hypoxic brain endothelial cells

Lipidoid nanoparticles (LNPs) are clinically successful carriers for nucleic acid delivery to liver and muscle targets. Their ability to load and deliver small molecule drugs has not been reported yet. We propose that the delivery of adenosine triphosphate (ATP) to brain endothelial cells (BECs) lining the blood-brain barrier may increase cellular energetics of the injured BECs. We formulated and studied the physicochemical characteristics of ATP-loaded LNPs using the C12-200 ionizable cationic lipid and other helper lipids. Polyethylene glycol-dimyristoyl glycerol (PEG-DMG), one of the helper lipids, played a crucial role in maintaining colloidal stability of LNPs over time whereas the inclusion of both ATP and PEG-DMG maintained the colloidal stability of LNPs in the presence of serum proteins. ATP-LNPs formulated with PEG-DMG resulted in a 7.7- and 6.6-fold increased uptake of ATP into normoxic and hypoxic BECs, respectively. Altogether, our results demonstrate the potential of LNPs as a novel carrier for the delivery of small molecular mass actives to BECs--a CNS target. HighlightsO_LILNPs were formulated with ATP, a small molecule drug C_LIO_LIPEG-DMG plays a critical role in maintaining particle stability over tim C_LIO_LIATP and PEG-DMG play a critical role in maintaining particle stability in 10% serum C_LIO_LIATP-LNPs were internalized by normoxic and hypoxic brain endothelial cells (BECs) C_LIO_LILNP delivery to BECs broadens its applicability to CNS targets C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/487513v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1a315eaorg.highwire.dtl.DTLVardef@1f3d649org.highwire.dtl.DTLVardef@17989fdorg.highwire.dtl.DTLVardef@526ce2_HPS_FORMAT_FIGEXP M_FIG C_FIG