jm5019115_si_001.pdf (2.31 MB)
Design, Synthesis, and Biological Evaluation of Theranostic Vitamin–Linker–Taxoid Conjugates
journal contribution
posted on 2015-03-12, 00:00 authored by Jacob
G. Vineberg, Tao Wang, Edison S. Zuniga, Iwao OjimaNovel tumor-targeting theranostic
conjugates 1 and 2, bearing either a fluorine-labeled
prosthetic as a potential 18F-PET radiotracer (1) or a fluorescence probe
(2) for internalization studies in vitro, were designed
and synthesized. We confirmed efficient internalization of 2 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 1 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 1 molecules internalized into
cells via RME in the first 24 h period exert cytotoxic effect. The
observed selectivity of 1 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.