Design, Synthesis, and Biological Evaluation of Theranostic Vitamin–Linker–Taxoid Conjugates

Abstract

Novel tumor-targeting theranostic conjugates <b>1</b> and <b>2</b>, bearing either a fluorine-labeled prosthetic as a potential ¹⁸F-PET radiotracer (<b>1</b>) or a fluorescence probe (<b>2</b>) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of <b>2</b> in biotin-receptor positive (BR+) cancer cells via receptor-mediated endocytosis (RME) based on flow cytometry and confocal fluorescence microscopy (CFM) analyses, which exhibited very high specificity to BR+ cancer cells. The potency and cancer-cell selectivity of <b>1</b> were evaluated against MX-1, L1210FR and ID8 cancer cells (BR+) as well as L1210 cells and WI38 normal human lung fibroblast cells (biotin-receptor negative: BR−). In particular, we designed and performed an assay in the presence of glutathione ethyl ester (GSH-OEt) wherein only <b>1</b> molecules internalized into cells via RME in the first 24 h period exert cytotoxic effect. The observed selectivity of <b>1</b> was remarkable, with 2 orders of magnitude difference in IC₅₀ values between BR+ cancer cells and WI38 cells, demonstrating a salient feature of this tumor-targeted drug delivery system