LDL-mimetic lipid nanoparticles prepared by surface KAT ligation for in vivo MRI of atherosclerosis

Fracassi, Alessandro (ETH Zürich, Zurich, Switzerland) ; Cao, Jianbo (University of Pennsylvania, Philadelphia, USA) ; Yoshizawa-Sugata, Naoko (Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) ; Toth, Éva (Université d’Orléans, Orléans, France) ; Archer, Corey (ETH Zürich, Zürich, Switzerland) ; Gröninger, Olivier (ETH Zürich, Zürich, Switzerland) ; Ricciotti, Emanuela (University of Pennsylvania, Philadelphia, USA) ; Tang, Soon Yew (University of Pennsylvania, Philadelphia, USA) ; Handschin, Stephan (ETH Zurich, Zürich, Switzerland) ; Bourgeois, Jean-Pascal (School of Engineering and Architecture (HEIA-FR), HES-SO // University of Applied Sciences Western Switzerland) ; Ray, Ankita (ETH Zürich, Zürich, Switzerland) ; Liosi, Korinne (ETH Zürich, Zürich, Switzerland) ; Oriana, Sean (ETH Zürich, Zürich, Switzerland) ; Stark, Wendelin (ETH Zürich, Zürich, Switzerland) ; Masai, Hisao (Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) ; Zou, Rong (University of Pennsylvania, Philadelphia, USA) ; Yamakoshi, Yoko (ETH Zürich, Zurich, Switzerland)

Low-density lipoprotein (LDL)-mimetic lipid nanoparticles (LNPs), decorated with MRI contrast agents and fluorescent dyes, were prepared by the covalent attachment of apolipoprotein-mimetic peptide (P), Gd(III)-chelate (Gd), and sulforhodamine B (R) moieties on the LNP surface. The functionalized LNPs were prepared using the amide-forming potassium acyltrifluoroborate (KAT) ligation reaction. The KAT groups on the surface of LNPs were allowed to react with the corresponding hydroxylamine (HA) derivatives of P and Gd to provide bi-functionalized LNPs (PGd-LNP). The reaction proceeded with excellent yields, as observed by ICP-MS (for B and Gd amounts) and MALDI-TOF-MS data, and did not alter the morphology of the LNPs (mean diameter: ca. 50 nm), as shown by DLS and cryoTEM analyses. With the help of the efficient KAT ligation, a high payload of Gd(III)-chelate on the PGd-LNP surface (ca. 2800 Gd atoms per LNP) was successfully achieved and provided a high r1 relaxivity (r1 = 22.0 s−1 mM−1 at 1.4 T/60 MHz and 25 °C; r1 = 8.2 s−1 mM−1 at 9.4 T/400 MHz and 37 °C). This bi-functionalized PGd-LNP was administered to three atherosclerotic apoE−/− mice to reveal the clear enhancement of atherosclerotic plaques in the brachiocephalic artery (BA) by MRI, in good agreement with the high accumulation of Gd in the aortic arch as shown by ICP-MS. The parallel in vivo MRI and ex vivo studies of whole mouse cryo-imaging were performed using triply functionalized LNPs with P, Gd, and R (PGdR-LNP). The clear presence of atherosclerotic plaques in BA was observed by ex vivo bright field cryo-imaging, and they were also observed by high emission fluorescent imaging. These directly corresponded to the enhanced tissue in the in vivo MRI of the identical mouse.


Article Type:
scientifique
Faculty:
Ingénierie et Architecture
School:
HEIA-FR
Institute:
ChemTech - Institut des technologies chimiques
Date:
2020-11
Pagination:
11 p.
Published in:
Chemical Science
Numeration (vol. no.):
2020, vol. 11, no. 44, pp. 11998-12008
DOI:
ISSN:
2041-6520
Appears in Collection:



 Record created 2020-12-15, last modified 2020-12-16

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