A bombesin-shepherdin radioconjugate designed for combined extra- and intracellular targeting

Area of Science:

• Nuclear medicine
• Radiopharmaceutical chemistry
• Oncology

Background:

• Targeted radiopharmaceuticals show promise for cancer diagnosis and therapy.
• Rapid radioactivity washout from tumors limits the efficacy of current radiopeptides.
• Internalizing radiopeptides combined with intracellular targets could potentially reduce washout.

Purpose of the Study:

• To investigate the combination of internalizing radiopeptides with intracellular targeting agents.
• To reduce or decelerate radioactivity externalization from cancer cells by enabling intracellular interactions.
• To develop a novel radioconjugate for enhanced cancer imaging and therapy.

Main Methods:

• Utilized the "click-to-chelate" approach to combine a 99mTc-tricarbonyl core with bombesin for extracellular targeting.
• Incorporated peptidic inhibitors of cytosolic heat shock 90 protein (Hsp90) for intracellular targeting.
• Evaluated receptor-specific uptake and cellular washout of the multifunctional radioconjugate.

Main Results:

• Confirmed receptor-specific uptake of the multifunctional radioconjugate.
• Observed no improvement in the cellular washout of radioactivity.
• Hypothesized that endosomal trapping or lysosomal degradation may account for the lack of improvement.

Conclusions:

• The developed radioconjugate demonstrated specific tumor targeting but failed to mitigate radioactivity washout.
• Further investigation is needed to overcome intracellular retention challenges.
• Strategies to prevent endosomal trapping or lysosomal degradation are crucial for improving radiopeptide efficacy.