Chitosan-based multimodal polymeric nanoparticles targeting pancreatic β-cells

Abstract

Multimodal in vivo imaging of pancreatic islets might improve monitoring of endocrine grafts upon implantation, helping clinical validation of new regenerative therapies based on the replacement of β-cells in type 1 diabetes affected patients. Herein, the generation of chitosan-based multimodal diagnostic nanoparticles (NPs) able to target β-cells is described. The NPs, composed of chitosan (CH) and γ-poly-glutamic-acid (γ-PGA) with different “clickable” functional groups were chemoselectively decorated at the surface with Exendin-4 (Ex4), a ligand of glucagon-like peptide 1 (GLP-1) β-cell receptors, and with a DOTA containing linker, to chelate diagnostic radioisotopes. Furthermore, the NPs were conjugated with IRDye®800CW for multispectral optoacoustic tomography (MSOT). The affinity of Ex4 decorated NPs towards GLP-1R was confirmed by competitive flow cytometry tests. The detectability of the NPs labeled with IRDye®800CW and Ex4 in MSOT experiments was demonstrated. In vivo biodistribution of Ex4 decorated NPs labelled with Ga-68 was studied with positron emission tomography (PET) experiments in mice. Specific binding to GLP-1 receptor expressing tissue was demonstrated in autoradiography experiments, showing potential of the multimodal NPs for specifically targeting β-cells.

Keywords

• Chitosan
• GLP-1R targeting
• Beta-cell targeting
• Exendin-4
• Multimodal imaging
• Diagnostic nanoparticles