A Dual Targeting Drug Delivery System for Penetrating Blood-Brain Barrier and Selectively Delivering siRNA to Neurons for Alzheimer's Disease Treatment.

Abstract

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.

• Authors: Chi Zhang, Zhichun Gu, Long Shen, Xianyan Liu, Houwen Lin
• Journal: Current pharmaceutical biotechnology (Curr Pharm Biotechnol) Vol. 18 Issue 14 Pg. 1124-1131 ( 2017) ISSN: 1873-4316 [Electronic] Netherlands
• PMID: 29484985 (Publication Type: Journal Article)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Drug Carriers
• RNA, Small Interfering
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Alzheimer Disease (genetics, therapy)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, genetics)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors, genetics)
• Blood-Brain Barrier (metabolism)
• Drug Carriers (chemistry)
• Drug Delivery Systems (methods)
• Gene Knockdown Techniques
• Humans
• Mice, Nude
• Molecular Targeted Therapy
• Nanoparticles (chemistry)
• Neurons (metabolism)
• PC12 Cells
• Permeability
• RNA, Small Interfering (administration & dosage, genetics)
• Rats