posted on 2021-09-06, 16:33authored byMaxime Siemons, Kaat Luyten, Ladan Khodaparast, Laleh Khodaparast, Joan Lecina, Filip Claes, Rodrigo Gallardo, Michel Koole, Meine Ramakers, Joost Schymkowitz, Guy Bormans, Frederic Rousseau
Amyloid-like aggregation
of proteins is induced by short amyloidogenic
sequence segments within a specific protein sequence resulting in
self-assembly into β-sheets. We recently validated a technology
platform in which synthetic amyloid peptides (“Pept-ins”)
containing a specific aggregation-prone region (APR) are used to induce
specific functional knockdown of the target protein from which the
APR was derived, including bacterial, viral, and mammalian cell proteins.
In this work, we investigated if Pept-ins can be used as vector probes
for in vivo Positron Emission Tomography (PET) imaging
of intracellular targets. The radiolabeled Pept-ins [68Ga]Ga-NODAGA-PEG4-vascin (targeting VEGFR2) and [68Ga]Ga-NODAGA-PEG2-P2 (targeting E. coli) were evaluated as PET probes. The Pept-in
based radiotracers were cross-validated in a murine tumor and muscle
infection model, respectively, and were found to combine target specificity
with favorable in vivo pharmacokinetics. When the
amyloidogenicity of the interacting region of the peptide is suppressed
by mutation, cellular uptake and in vivo accumulation
are abolished, highlighting the importance of the specific design
of synthetic Pept-ins. The ubiquity of target-specific amyloidogenic
sequence segments in natural proteins, the straightforward sequence-based
design of the Pept-in probes, and their spontaneous internalization
by cells suggest that Pept-ins may constitute a generic platform for in vivo PET imaging of intracellular targets.