Background: Alzheimer’s disease (AD) is one of most serious threats to human beings,
however, the treatment is hindered by blood-brain barrier and poor intra-brain cell selectivity.
Methods: In this study, we developed a novel dual targeting drug delivery system by modification of
NL4 peptide and apolipoprotein A-I (ApoA-I) onto dendrimer particles that may efficiently deliver
siRNA into neuron cells to down-regulate BACE1 and inhibit Aβ formation. The constructed ANNP/
siRNA was approximately 79.26 nm with a spherical structure and a zeta potential of 3.53 mV. At N/P
ratio of 10, the siRNA could be completely packaged into particles to avoid degradation by RNAase.
Results: In vitro, the modification with ApoA-I considerably increased bEnd.3 cell uptake and NL-4
considerably increased PC12 cell uptake. As a result, ANNP/siRNA showed higher uptake in both the
cells. In addition, ANNP/siRNA could efficiently penetrate through bEnd.3 monolayers, which was
2.4-fold higher than unmodified complexes. In PC12 cells, the ANNP/siRNA could escape from endosomes
and transport into cytoplasm after 8 h incubation, resulting in 87.5% BACE1 gene knockdown
capacity, which was better than PEI. Additionally, the particles showed low cytotoxicity to both
bEnd.3 and PC12 cells.
Conclusion: In conclusion, this study preliminarily demonstrated that ApoA-I and NL4 dual modified
dendrimer nanoparticles were efficient carriers for siRNA delivery to AD bearing brain.