A Modular Supramolecular Peptide Platform Reveals Atomic-Number-Dependent Mechanisms Driving Radioenhancement

Area of Science:

• Nanomedicine
• Radiation Oncology
• Bioconjugate Chemistry

Background:

• Optimizing high-Z nanoparticles for cancer radiotherapy is hindered by inconsistent comparisons and unclear nanoscale mechanisms.
• The assumption of a uniform increase in radioenhancement with atomic number may be an oversimplification.

Purpose of the Study:

• To introduce a versatile supramolecular peptide platform for standardized comparison of gadolinium (Gd), bismuth (Bi), and hafnium (Hf) as radioenhancers.
• To elucidate the nanoscale mechanisms governing metal-dependent radioenhancement and explore theranostic applications.

Main Methods:

• Development of a self-assembling peptide heterodimer (E3-K3) platform with a chelator (DOTAGA) and variable antibody domains (VHH) for targeted delivery.
• Systematic in vitro and in vivo analyses in HER2+ breast cancer and multiple myeloma models.
• Evaluation of DNA damage, reactive oxygen species generation, clonogenic survival, and tumor control.

Main Results:

• Radioenhancement efficacy correlated with atomic number but not linearly, influenced by metal physicochemical properties.
• Gd- and Bi-loaded nanoparticles significantly enhanced tumor control, with Bi showing superior efficacy.
• Gd-based constructs enabled MRI-guided radioligand therapy, demonstrating theranostic potential.

Conclusions:

• The study elucidates fundamental physical mechanisms of metal-dependent radioenhancement at the nanoscale.
• A broadly applicable theranostic approach with translational implications for personalized radiation oncology was established.