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.
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Authors | Jacob G Vineberg, Tao Wang, Edison S Zuniga, Iwao Ojima |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 58
Issue 5
Pg. 2406-16
(Mar 12 2015)
ISSN: 1520-4804 [Electronic] United States |
PMID | 25654690
(Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Receptors, Growth Factor
- Taxoids
- Vitamins
- biotin receptor
- Biotin
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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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