Development of Novel Integrin α_vβ₃‑Targeted Radioligand for Enhanced Tumor Accumulation

Area of Science:

• Radiopharmaceutical chemistry
• Molecular imaging
• Cancer biology

Background:

• Effective tumor delivery of radioligands is critical for cancer diagnosis and therapy.
• Integrin αvβ3 is a promising target for cancer treatment, necessitating radioligands with high tumor accumulation.
• Albumin binders (ALB) and dual amino acid linkers can enhance radioligand tumor uptake.

Purpose of the Study:

• To develop and evaluate novel integrin αvβ3-targeted radioligands with improved tumor accumulation.
• To assess the impact of dual amino acid linkers combined with an albumin binder on radioligand properties.
• To compare the albumin-binding affinity and tumor accumulation of newly developed radioligands.

Main Methods:

• Synthesis of two novel 111In-labeled radioligands: [111In]-In-RGD-DA6 (dual amino acid linkers + ALB) and [111In]-In-RGD-DA1 (ALB only).
• Albumin-binding assays to determine binding affinity.
• In vivo biodistribution studies in relevant models to evaluate tumor accumulation.

Main Results:

• [111In]-In-RGD-DA6 demonstrated significantly higher albumin-binding affinity compared to [111In]-In-RGD-DA1 and a control ([111In]-In-DOTA-c-(RGDfK)).
• [111In]-In-RGD-DA6 exhibited superior tumor accumulation in biodistribution studies compared to the other two radioligands.
• The combination of dual amino acid linkers and ALB moiety effectively enhanced tumor targeting.

Conclusions:

• The novel radioligand [111In]-In-RGD-DA6 shows enhanced albumin-binding affinity and tumor accumulation.
• This compound holds significant potential as an improved integrin αvβ3-targeted radioligand for cancer imaging and therapy.
• Dual amino acid linkers combined with albumin binders represent a promising strategy for optimizing radioligand delivery.