Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release
| Autor: | Jin Chen, Larisa V. Kuznetsova, Shuyi Chen, Xianrui Zhao, Stanislaus S. Wong, Jingyi Chen, Iwao Ojima |
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| Rok vydání: | 2010 |
| Předmět: |
Cell Survival
Biomedical Engineering Biotin Pharmaceutical Science Antineoplastic Agents Bioengineering Endocytosis Article chemistry.chemical_compound Drug Delivery Systems Cell Line Tumor Neoplasms Humans Vitamin receptor Receptor Pharmacology Leukemia Cytotoxins Organic Chemistry Cell biology chemistry Biochemistry Drug delivery Taxoids Target protein Linker Biotechnology Conjugate |
| Zdroj: | Bioconjugate Chemistry. 21:979-987 |
| ISSN: | 1520-4812 1043-1802 |
| Popis: | An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface and (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate, drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3, and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed), and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism-based tumor-targeting drug delivery system will find a range of applications. |
| Databáze: | OpenAIRE |
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