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Synthesis and preclinical evaluation of functionalized 18F-nanoliposomes for Alzheimer’s disease

Rokka, Johanna, Snellman, Anniina, Kaasalainen, Martti, Salonen, Jarno, Zona, Critiano, La Ferla, Barbara, Re, Francesca, Masserini, Massimo, Forsback, Sarita, Lopez-Picon, Francisco, Rinne, Joha O, Haaparanta Solin, Merja and Solin, Olof (2016) Synthesis and preclinical evaluation of functionalized 18F-nanoliposomes for Alzheimer’s disease. European Journal of Pharmaceutical Sciences.


Nanoliposomes (NLs) are an applicable platform for drug delivery and imaging agent carrier in Alzheimer’s disease (AD). Functional groups can be attached to the surface of NLs in order to bind the NLs to specific targets or enhance their transport to the tissue of interest. The formation of β-amyloid plaques is a characteristic hallmark of AD. In vitro studies have shown that NLs functionalized with phosphatidic acid (PA) and curcumin derivate (Curc) bind to β-amyloid fibrils but have low blood-brain barrier (BBB) penetration. ApoE peptide residue (mApoE) functionalization has been shown to increase liposome binding to the low density lipoprotein receptors in brain capillary endothelial cells in vitro, suggesting that mApoE functionalization increases the BBB penetration of liposomes. The aim of the present study was to synthesize 18F-labeled anionic functionalized NLs and evaluate their biological behavior, BBB penetration, and β-amyloid binding in AD mouse models.
Methods: Functionalized anionic, PA-18F-NLs and Curc-18F-NLs with or without additional mApoE functionalization were produced using nucleophilic 18F-fluorination and thin film hydration. Two labeling approaches were used: either the core lipid was labeled or 18F-treg-curcumin was encapsulated inside the liposome. The biodistribution and β-amyloid plaque-binding ability of synthesized 18F-NLs were studied in AD mouse models and wild-type control mice using in vivo PET imaging and ex vivo brain autoradiography.
Results: Functionalized 18F-NLs were successfully synthesized using the two 18F-labeling approaches. High blood 18F-activity was measured with PA-18F-NLs and Curc-18F-NLs but brain uptake was low in AD mouse models. Functionalization with mApoE did not increase the initial brain uptake one hour after tracer injection, but ex vivo brain autoradiographs showed radioactive “hot spots” all over the brain. The PA-mApoE-NL and Curc-mApoE-NL 18F-treg-curcumins were not stable in mice in vivo, and the biodistribution of these NLs was identical to that of 18F-treg-curcumin alone.
Conclusions: Functional 18F-NLs were successfully synthesized and evaluated in AD mouse models, and the functional group affected their biodistribution. The synthesis techniques introduced in this study can be utilized to study the biological behavior of functionalized liposomes with PET.

Item Type: Article
Keywords: Positron emission tomography (PET), nucleophilic 18F-fluorination, functionalized nanoliposomes, Alzheimer’s disease, β-amyloid plaques.
Date Deposited: 04 May 2016 23:45
Last Modified: 04 May 2016 23:45


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