Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides

Adrien Chastel, Dennis J. Worm, Isabel D. Alves, Delphine Vimont, Melina Petrel, Samantha Fernandez, Philippe Garrigue, Philippe Fernandez, Elif Hindié, Annette G. Beck-Sickinger, Clément Morgat
EJNMMI Res. 2020-03-02; 10(1):
DOI: 10.1186/s13550-020-0612-8

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Chastel A(1)(2)(3), Worm DJ(4), Alves ID(5), Vimont D(2)(3), Petrel M(6), Fernandez S(7)(8), Garrigue P(7)(8), Fernandez P(1)(2)(3), Hindié E(1)(2)(3),
Beck-Sickinger AG(4), Morgat C(9)(10)(11).

Author information:
(1)Department of Nuclear Medicine, University Hospital of Bordeaux, F-33076, Bordeaux, France.
(2)University of Bordeaux, INCIA UMR 5287, F-33400, Talence, France.
(3)CNRS, INCIA UMR 5287, F-33400, Talence, France.
(4)Institute of Biochemistry, Faculty of Life Sciences, Leipzig University,
Brüderstr. 34, 04103, Leipzig, Germany.
(5)Institute of Chemistry & Biology of Membranes & Nano-objects (CBMN), CNRS UMR 5248, University of Bordeaux, F-33600, Pessac, France.
(6)University of Bordeaux, Bordeaux Imaging Center, F-33000, Bordeaux, France.
(7)Aix-Marseille University, INSERM, Institut National de la Recherche
Agronomique, Centre de Recherche en Cardiovasculaire et Nutrition, 13385, Marseille, France.
(8)Aix-Marseille University, Centre Européen de Recherche en Imagerie Médicale, 13005, Marseille, France.
(9)Department of Nuclear Medicine, University Hospital of Bordeaux, F-33076, Bordeaux, France. .
(10)University of Bordeaux, INCIA UMR 5287, F-33400, Talence, France. .
(11)CNRS, INCIA UMR 5287, F-33400, Talence, France. .

BACKGROUND: Targeting G protein-coupled receptors on the surface of cancer cells with peptide ligands is a promising concept for the selective tumor delivery of therapeutically active cargos, including radiometals for targeted radionuclide therapy (TRT). Recently, the radiolanthanide terbium-161 (161Tb) gained significant interest for TRT application, since it decays with medium-energy β-radiation but also emits a significant amount of conversion and Auger electrons with short tissue penetration range. The therapeutic efficiency of radiometals
emitting Auger electrons, like 161Tb, can therefore be highly boosted by an additional subcellular delivery into the nucleus, in order to facilitate maximum dose deposition to the DNA. In this study, we describe the design of a multifunctional, radiolabeled neuropeptide-Y (NPY) conjugate, to address radiolanthanides to the nucleus of cells naturally overexpressing the human Y1 receptor (hY1R). By using solid-phase peptide synthesis, the hY1R-preferring [F7,P34]-NPY was modified with a fatty acid, a cathepsin B-cleavable linker, followed by a nuclear localization sequence (NLS), and a DOTA chelator (compound pb12). In this proof-of-concept study, labeling was performed with either native terbium-159 (natTb), as surrogate for 161Tb, or with indium-111 (111In).

RESULTS: [natTb]Tb-pb12 showed a preserved high binding affinity to endogenous hY1R on MCF-7 cells and was able to induce receptor activation and internalization similar to the hY1R-preferring [F7,P34]-NPY. Specific internalization of the 111In-labeled conjugate into MCF-7 cells was observed, and importantly, time-dependent nuclear uptake of 111In was demonstrated. Study of
metabolic stability showed that the peptide is insufficiently stable in human plasma. This was confirmed by injection of [111In]In-pb12 in nude mice bearing MCF-7 xenograft which showed specific uptake only at very early time point.

CONCLUSION: The multifunctional NPY conjugate with a releasable DOTA-NLS unit represents a promising concept for enhanced TRT with Auger electron-emitting radiolanthanides. Our research is now focusing on improving the reported concept with respect to the poor plasmatic stability of this promising radiopeptide.


Auteurs Bordeaux Neurocampus