Evaluation of targeting α_Vβ₃ in breast cancers using RGD peptide-based agents

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• HER2-positive and triple-negative breast cancer (TNBC) patients face high risks of metastatic and therapy-resistant disease.
• The α_Vβ₃ integrin is implicated in breast cancer (BC) progression and metastasis.
• Targeted alpha therapy (TAT) offers a promising approach for delivering potent radioactive payloads to cancer cells.

Purpose of the Study:

• To investigate the potential of α_Vβ₃-targeted peptides for delivering radioactive payloads to BC tumors.
• To assess the pharmacokinetic profile of the TAT agent [²²⁵Ac]Ac-DOTA-cRGDfK dimer and its in vivo generated decay daughters.
• To evaluate the biodistribution and dosimetry of the TAT agent and its decay products in preclinical models.

Main Methods:

• Western blot analysis to confirm α_Vβ₃ expression in HER2-positive and TNBC cell lines.
• Pharmacokinetic evaluation of a surrogate agent ([¹¹¹In]In-DOTA-cRGDfK dimer) in subcutaneous mouse tumor models.
• In vivo pharmacokinetic and dosimetric analysis of the TAT agent ([²²⁵Ac]Ac-DOTA-cRGDfK dimer) and its decay daughters in healthy mice.

Main Results:

• Selective uptake of the targeted peptide was observed in tumors expressing α_Vβ₃ on tumor cells and/or neovasculature.
• Pharmacokinetic studies revealed rapid tumor accumulation and clearance from non-target organs.
• Dosimetric analysis indicated the highest radiation absorbed dose to the kidneys, including contributions from in vivo generated decay daughters.

Conclusions:

• α_Vβ₃-targeted peptides demonstrate potential for delivering radioactive payloads to diverse breast cancer subtypes.
• The study provides crucial pharmacokinetic and dosimetric data for the [²²⁵Ac]Ac-DOTA-cRGDfK dimer TAT agent.
• Understanding the dosimetry of decay daughters is essential for optimizing targeted alpha therapy safety and efficacy.