A Small Molecule Drug-Based Ru(II) Polypyridine Mass-Tag for Multimodal Imaging of Tissue Samples.

Area of Science:

• Biochemistry
• Analytical Chemistry
• Molecular Imaging

Background:

• Mass spectrometry imaging (MSI) enables spatially resolved multiomics analysis of tissues.
• Current MSI proteomics face challenges like low ionization efficiency and signal interference.
• On-tissue mass-tag labeling (OTMT) uses affinity agents with cleavable reporter groups (mass-tags, MTs) to enhance MSI analysis.

Purpose of the Study:

• To introduce a new class of MTs utilizing small-molecule inhibitors as targeting motifs.
• To present PARPi-MT, a novel bimodal imaging agent for poly-(ADP-ribose) polymerase 1 (PARP1).
• To expand the versatility and applications of OTMT in MSI.

Main Methods:

• Developed PARPi-MT comprising a photocleavable, luminescent Ruthenium(II)-based reporter and the PARP inhibitor Olaparib.
• Utilized PARPi-MT for targeted bimodal imaging of PARP1 in H446 xenograft tumor and mouse brain sections.
• Employed desorption electrospray ionization (DESI)-MSI and fluorescence microscopy for imaging.

Main Results:

• Demonstrated successful targeted bimodal imaging of PARP1 using PARPi-MT.
• Showcased the effectiveness of small-molecule inhibitors as binding motifs in OTMT.
• Highlighted the advantages of the Ru(II)-based reporter, including distinct isotopic signatures and multimodal imaging capabilities.

Conclusions:

• Small-molecule inhibitors offer expanded design versatility for OTMT compared to antibody-based MTs.
• PARPi-MT provides a novel tool for targeted imaging of PARP1 with MSI and fluorescence microscopy.
• The developed Ru(II)-based reporter group enhances MSI analysis through unique isotopic properties and multimodal imaging potential.