Fatty Acid-Based Strategy for Efficient Brain Targeted Gene Delivery

To investigate a fatty acid-based strategy for efficient brain targeted gene delivery and to understand mechanism(s) of this small molecule-mediated brain gene delivery strategy. A series of fatty acids (FAs) were conjugated with polyethylenimine (PEI25k). A near-infrared fluorescence probe, IR820, was used to study in vivo and ex vivo brain targeting ability of these fatty acid-PEI conjugates (FA-PEIs). Brain uptake of FA-PEI25k/rhodamine-6-isothiocyanate (RITC)-labeled DNA nanoparticles was investigated via a fluorescence imaging method. Moreover, pEGFP was used as a model gene to study in vitro and in vivo transfection effect of the ideal FA-PEI25k conjugate. FA modification did not have interference with the complexation between DNA and the PEI25k. The FA-PEI25k conjugates showed excellent brain targeting ability compared with unmodified PEI25k. Among these FA-PEI25k conjugates studied, myristic acid (MC)-PEI25k showed sustained brain distribution profile and higher brain DNA uptake. Furthermore, MC-PEI(25k/)pEGFP nanoparticles was able to achieve efficient in vitro and in vivo gene transfection. GFP expression was observed at different brain regions in vivo. These results demonstrated that the small molecule fatty acid, particularly myristic acid-based brain gene delivery strategy, is promising to mediate efficient gene transfection in the brain.