title: Design, synthesis, and biological evaluation of theranostic vitamin-linker-taxoid conjugates.
abstract: Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-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.
authors: Department of Chemistry and ‡Institute of Chemical Biology & Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
authors: Jacob G
authors: JG
authors: Vineberg
authors: Tao
authors: T
authors: Wang
authors: Edison S
authors: ES
authors: Zuniga
authors: Iwao
authors: I
authors: Ojima
mesh_terms: D000818:Animals; D001710:Biotin / Q000378:metabolism; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D015195:Drug Design; D004705:Endocytosis; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology*; D014815:Vitamins / Q000737:chemistry*
chemical_list: D017978:Receptors, Growth Factor; D043823:Taxoids; D014815:Vitamins; C052136:biotin receptor; D001710:Biotin
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