Implications of albumin binding for targeted radiopharmaceuticals

Besides optimizing the vector molecule for its interaction toward the respective target protein, a modern tool in the field of radiopharmaceutical cancer therapy is the introduction of albumin-binding moieties to modulate the pharmacokinetic properties [1]. Basically, the approach aims at increasing the time-integral uptake of radioactivity in the tumor, which consequently increases the total radiation dose delivered to the tumor and thus, might improve the therapeutic outcome. In contrast, binding to albumin goes along with a prolonged blood circulation time and thus, a higher radiation dose to healthy tissues, in particular the red bone marrow. Vector molecules of various targets, including folate receptor, prostate specific membrane antigen (PSMA), and fibroblast activation protein (FAP), were equipped with albumin-binding moieties and promising preclinical studies were reported. However, the actual implications of binding to albumin appear less or even erroneously understood. In this context, the protracted tumor uptake is an important aspect, which originates from lowering the unbound fraction of the radioligand in the blood. Moreover, considering the free drug hypothesis [2], the usually observed gain in tumor uptake requires another tumor uptake mechanism of the albumin-bound radioligand to be operational and is not a result of the prolonged blood circulation time.
Based on our own data to albumin-binding radioligands of the somatostatin receptor subtype 2 (SST2) [3], the talk will give insight into the pharmacokinetic implications of albumin binding with a special focus on the relation of the binding affinity to albumin and the resulting biodistribution of the radioligand, which is also of importance for the radiation-induced toxicity to healthy tissues.

References:

1. Brandt M et al.: Nucl. Med. Biol. 2019, 70: 46–52.
2. Smith D A, Di L, Kerns E H: Nat. Rev. Drug Discov. 2010, 9(12): 929–939.
3. Brandt F et al.: J. Med. Chem. 2022, 65(1): 710–733.