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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.
AuthorsJacob G Vineberg, Tao Wang, Edison S Zuniga, Iwao Ojima
JournalJournal of medicinal chemistry (J Med Chem) Vol. 58 Issue 5 Pg. 2406-16 (Mar 12 2015) ISSN: 1520-4804 [Electronic] United States
PMID25654690 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Receptors, Growth Factor
  • Taxoids
  • Vitamins
  • biotin receptor
  • Biotin
Topics
  • Animals
  • Biotin (metabolism)
  • Cells, Cultured
  • Drug Delivery Systems
  • Drug Design
  • Endocytosis
  • Fibroblasts (cytology, drug effects)
  • Flow Cytometry
  • Humans
  • Lung (cytology, drug effects)
  • Mice
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Molecular Targeted Therapy
  • Neoplasms (drug therapy)
  • Receptors, Growth Factor (metabolism)
  • Taxoids (chemistry, pharmacology)
  • Vitamins (chemistry)

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