In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System

Author(s): Chi Zhang, Zhichun Gu, Long Shen, Xianyan Liu, Houwen Lin*

Journal Name: Current Pharmaceutical Biotechnology

Volume 20 , Issue 1 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: To deliver drugs to treat Alzheimer’s Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons.

Methods: Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant.

Results and Conclusion: After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

Keywords: Alzheimer's Disease (AD), BACE1 RNA, AD targeting, siRNA, Blood Brain Barrier (BBB), nanoparticles.

Gregori, M.; Masserini, M.; Mancini, S. Nanomedicine for the treatment of Alzheimer’s disease. Nanomedicine (Lond.), 2015, 10(7), 1203-1218.
Gao, H. Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm. Sin. B, 2016, 6(4), 268-286.
Gao, H.; Pang, Z.; Jiang, X. Targeted delivery of nano-therapeutics for major disorders of the central nervous system. Pharm. Res., 2013, 30(10), 2485-2498.
Gao, H. Perspectives on dual targeting delivery systems for brain tumors. J. Neuroimmune Pharmacol., 2017, 12(1), 6-16.
Nath, S.; Agholme, L.; Kurudenkandy, F.R.; Granseth, B.; Marcusson, J.; Hallbeck, M. Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. J. Neurosci., 2012, 32(26), 8767-8777.
Zhang, C.; Gu, Z.; Shen, L.; Liu, X.; Lin, H. A dual targeting drug delivery system for penetrating blood brain barrier and selectively delivering siRNA to neurons for Alzheimer’s disease treatment. Curr. Pharm. Biotechnol., 2018, 18(14), 1124-1131.
Zensi, A.; Begley, D.; Pontikis, C.; Legros, C.; Mihoreanu, L.; Buchel, C.; Kreuter, J. Human serum albumin nanoparticles modified with apolipoprotein A-I cross the blood-brain barrier and enter the rodent brain. J. Drug Target., 2010, 18(10), 842-848.
Xie, Y.; Tisi, M.A.; Yeo, T.T.; Longo, F.M. Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects. J. Biol. Chem., 2000, 275(38), 29868-29874.
Zeng, J.; Too, H.P.; Ma, Y.; Luo, E.S.; Wang, S. A synthetic peptide containing loop 4 of nerve growth factor for targeted gene delivery. J. Gene Med., 2004, 6(11), 1247-1256.
Allaman, I.; Gavillet, M.; Belanger, M.; Laroche, T.; Viertl, D.; Lashuel, H.A.; Magistretti, P.J. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal viability. J. Neurosci., 2010, 30(9), 3326-3338.
He, Z.; Guo, J.L.; McBride, J.D.; Narasimhan, S.; Kim, H.; Changolkar, L.; Zhang, B.; Gathagan, R.J.; Yue, C.; Dengler, C.; Stieber, A.; Nitla, M.; Coulter, D.A.; Abel, T.; Brunden, K.R.; Trojanowski, J.Q.; Lee, V.M. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med., 2018, 24(1), 29-38.
Cai, H.; Wang, Y.; McCarthy, D.; Wen, H.; Borchelt, D.R.; Price, D.L.; Wong, P.C. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat. Neurosci., 2001, 4(3), 233-234.
Zohar, O.; Cavallaro, S.; D’Agata, V.; Alkon, D.L. Quantification and distribution of beta-secretase alternative splice variants in the rat and human brain. Brain Res. Mol. Brain Res., 2003, 115(1), 63-68.
Vassar, R. Beta-secretase (BACE) as a drug target for Alzheimer’s disease. Adv. Drug Deliv. Rev., 2002, 54(12), 1589-1602.
Zheng, X.; Zhang, C.; Guo, Q.; Wan, X.; Shao, X.; Liu, Q.; Zhang, Q. Dual-functional nanoparticles for precise drug delivery to Alzheimer’s disease lesions: Targeting mechanisms, pharmacodynamics and safety. Int. J. Pharm., 2017, 525(1), 237-248.
Hu, G.; Zhang, H.; Zhang, L.; Ruan, S.; He, Q.; Gao, H. Integrin-mediated active tumor targeting and tumor microenvironment response dendrimer-gelatin nanoparticles for drug delivery and tumor treatment. Int. J. Pharm., 2015, 496(2), 1057-1068.
Zhang, H.; Wu, T.; Yu, W.; Ruan, S.; He, Q.; Gao, H. Ligand size and conformation affect the behavior of nanoparticles coated with in vitro and in vivo protein corona. ACS Appl. Mater. Interfaces, 2018, 10(10), 9094-9103.
Liu, R.; Xiao, W.; Hu, C.; Xie, R.; Gao, H. Theranostic size-reducible and no donor conjugated gold nanocluster fabricated hyaluronic acid nanoparticle with optimal size for combinational treatment of breast cancer and lung metastasis. J. Control. Release, 2018, 278, 127-139.
Hu, C.; Cun, X.; Ruan, S.; Liu, R.; Xiao, W.; Yang, X.; Yang, Y.; Yang, C.; Gao, H. Enzyme-triggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy. Biomaterials, 2018, 168, 64-75.
Ruan, S.; Hu, C.; Tang, X.; Cun, X.; Xiao, W.; Shi, K.; He, Q.; Gao, H. Increased gold nanoparticle retention in brain tumors by in situ enzyme-induced aggregation. ACS Nano, 2016, 10(11), 10086-10098.
Xiao, W.; Xiong, J.; Zhang, S.; Xiong, Y.; Zhang, H.; Gao, H. Influence of ligands property and particle size of gold nanoparticles on the protein adsorption and corresponding targeting ability. Int. J. Pharm., 2018, 538(1-2), 105-111.
Ruan, S.; Qian, J.; Shen, S.; Chen, J.; Cun, X.; Zhu, J.; Jiang, X.; He, Q.; Gao, H. Non-invasive imaging of breast cancer using RGDyK functionalized fluorescent carbonaceous nanospheres. RSC Advances, 2015, 5(254), 28-36.
Gao, H.; He, Q. The interaction of nanoparticles with plasma proteins and the consequent influence on nanoparticles behavior. Expert Opin. Drug Deliv., 2014, 11(3), 409-420.
Gao, H.; Yang, Z.; Zhang, S.; Pang, Z.; Jiang, X. Internalization and subcellular fate of aptamer and peptide dual-functioned nanoparticles. J. Drug Target., 2014, 22(5), 450-459.
Gao, H.; Yang, Z.; Zhang, S.; Cao, S.; Shen, S.; Pang, Z.; Jiang, X. Ligand modified nanoparticles increases cell uptake, alters endocytosis and elevates glioma distribution and internalization. Sci. Rep., 2013, 3, 2534.
Liu, J.; Shapiro, J.I. Endocytosis and signal transduction: basic science update. Biol. Res. Nurs., 2003, 5(2), 117-128.
Gao, H.; Xiong, Y.; Zhang, S.; Yang, Z.; Cao, S.; Jiang, X. RGD and interleukin-13 peptide functionalized nanoparticles for enhanced glioblastoma cells and neovasculature dual targeting delivery and elevated tumor penetration. Mol. Pharm., 2014, 11(3), 1042-1052.
Ruan, S.; Qin, L.; Xiao, W.; Hu, C.; Zhou, Y.; Wang, R.; Sun, X.; Yu, W.; He, Q.; Gao, H. Acid-responsive transferrin dissociation and GLUT mediated exocytosis for increased blood-brain barrier transcytosis and programmed glioma targeting delivery. Adv. Funct. Mater., 2018, 28(30), 1802227.
Pang, Z.; Lu, W.; Gao, H.; Hu, K.; Chen, J.; Zhang, C.; Gao, X.; Jiang, X.; Zhu, C. Preparation and brain delivery property of biodegradable polymersomes conjugated with OX26. J. Control. Release, 2008, 128(2), 120-127.
Zhang, C.; Chen, J.; Feng, C.; Shao, X.; Liu, Q.; Zhang, Q.; Pang, Z.; Jiang, X. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer’s disease. Int. J. Pharm., 2014, 461(1-2), 192-202.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 22 March, 2019
Page: [56 - 62]
Pages: 7
DOI: 10.2174/1389201020666190204141046
Price: $65

Article Metrics

PDF: 47