Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Aug 12

PMID 35956909

Authors

Joseph Lau

Hwan Lee

Julie Rousseau

Francois Benard

Kuo-Shyan Lin

Affiliations

Soon will be listed here.

Abstract

Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology.

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