Tailoring Avidity through Morphology: Structure-Avidity Relationship in CD38-Binding Nanofiber Radiotracers

Area of Science:

• Biomaterials Science
• Nanotechnology
• Molecular Imaging

Background:

• Targeted molecular imaging agents are lacking for multiple myeloma (MM), impeding disease characterization and theranostics.
• CD38 is a key antigen expressed in multiple myeloma, making it a promising therapeutic and diagnostic target.

Purpose of the Study:

• To engineer a tunable platform of self-assembled peptide nanofibers targeting CD38 for MM.
• To establish a correlation between lipid tail length, nanofiber structure, and biological function.

Main Methods:

• Peptide nanofibers were engineered with varying lipid tail lengths (C4-C12).
• Supramolecular architecture was analyzed using cryo-electron microscopy (cryo-EM).
• Biological function, including CD38 avidity and cell-surface engagement, was evaluated in vitro. Nanofibers were radiolabeled with 64Cu.

Main Results:

• Lipid tail length dictates nanofiber supramolecular architecture and CD38 avidity.
• T12 nanofibers achieved sub-nanomolar affinity for CD38.
• Optimized nanofibers demonstrated pH-responsive cross-linking and superior cell-surface engagement compared to monomers.
• Nanofibers showed excellent serum stability, no toxicity, and efficient 64Cu radiolabeling.

Conclusions:

• Lipid tail length is a critical parameter for controlling nanofiber structure, avidity, and function.
• This work presents a robust and translatable platform for CD38-targeted imaging and therapy in CD38-positive malignancies.
• The developed nanofibers hold promise for advancing precision medicine in multiple myeloma.