Integrity of lipid nanocarriers in bloodstream and tumor quantified by near-infrared ratiometric FRET imaging in living mice.
Lipid nanocarriers are considered as promising candidates for drug delivery and cancer targeting because of their low toxicity, biodegradability and capacity to encapsulate drugs and/or contrasting agents. However, their biomedical applications are currently limited because of a poor understanding of their integrity in vivo. To address this problem, we report on fluorescent nano-emulsion droplets of 100nm size encapsulating lipophilic near-infrared cyanine 5.5 and 7.5 dyes with a help of bulky hydrophobic counterion tetraphenylborate. Excellent brightness and efficient Förster Resonance Energy Transfer (FRET) inside lipid NCs enabled for the first time quantitative fluorescence ratiometric imaging of NCs integrity directly in the blood circulation, liver and tumor xenografts of living mice using a whole-animal imaging set-up. This unique methodology revealed that the integrity of our FRET NCs in the blood circulation of healthy mice is preserved at 93% at 6h of post-administration, while it drops to 66% in the liver (half-life is 8.2h). Moreover, these NCs show fast and efficient accumulation in tumors, where they enter in nearly intact form (77% integrity at 2h) before losing their integrity to 40% at 6h (half-life is 4.4h). Thus, we propose a simple and robust methodology based on ratiometric FRET imaging in vivo to evaluate quantitatively nanocarrier integrity in small animals. We also demonstrate that nano-emulsion droplets are remarkably stable nano-objects that remain nearly intact in the blood circulation and release their content mainly after entering tumors.
Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, University of Strasbourg, 74 route du Rhin, 67401 Illkirch Cedex, France; Laboratory of Photonic Systems and Nonlinear Optics, Institute of Optics and Fine Mechanics, University of Setif 1, 19000, Algeria.
Redouane
R
Bouchaala
MN3T, Inserm U1109, LabEx Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, F-67200, France.
Luc
L
Mercier
Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, University of Strasbourg, 74 route du Rhin, 67401 Illkirch Cedex, France; Organic Chemistry Department, Chemistry Faculty, Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine.
Bohdan
B
Andreiuk
Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, University of Strasbourg, 74 route du Rhin, 67401 Illkirch Cedex, France.
Yves
Y
Mély
CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, University of Strasbourg, 74 route du Rhin, 67401 Illkirch Cedex, France.
Thierry
T
Vandamme
CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, University of Strasbourg, 74 route du Rhin, 67401 Illkirch Cedex, France. Electronic address: nanton@unistra.fr.
Nicolas
N
Anton
MN3T, Inserm U1109, LabEx Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, F-67200, France. Electronic address: jacky.goetz@inserm.fr.
Jacky G
JG
Goetz
Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, University of Strasbourg, 74 route du Rhin, 67401 Illkirch Cedex, France. Electronic address: andrey.klymchenko@unistra.fr.
Andrey S
AS
Klymchenko
D000818:Animals; D002232:Carbocyanines / Q000737:chemistry; D004655:Emulsions; D031541:Fluorescence Resonance Energy Transfer; D005456:Fluorescent Dyes / Q000737:chemistry; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000032:analysis* / Q000097:blood / Q000138:chemical synthesis; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry* / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000473:pathology; D061848:Optical Imaging; D010539:Permeability; D019265:Spectroscopy, Near-Infrared
C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D004655:Emulsions; D005456:Fluorescent Dyes; D008055:Lipids; D053769:Nanocapsules; C085321:cyanine dye 5
Enhanced permeability and retention; In vivo imaging; Lipid nanocarriers; Nanocarrier integrity; Near-infrared FRET; Tumor