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Apoptotic epidermal growth factor (EGF)-conjugated block copolymer micelles as a nanotechnology platform for targeted combination therapy.
The overexpression of epidermal growth factor receptor (EGFR) in human epithelial cancers has been associated with aggressive disease, poor patient prognosis, and a high incidence of metastases. In the present study, block copolymer micelles are conjugated with epidermal growth factor (EGF), which acts as both a targeting ligand for the drug carrier and an apoptotic factor against EGFR-overexpressing cancers. Drug-free EGF-conjugated micelles are shown to result in cell-cycle arrest at the G 1 phase and subsequent induction of cell-type-specific apoptosis in EGFR-overexpressing breast cancer cells as demonstrated by flow cytometric analysis. EGF delivered as EGF-conjugated micelles was found to be 13-fold more potent than free EGF; the IC 50 was decreased from 0.98 +/- 0.1 nM for free EGF to 0.076 +/- 0.01 nM for EGF micelles. The apoptotic micelles, however, are non-antiproliferative to cells expressing a low level of EGFR, suggesting that the apoptotic micelles have minimal or no toxicity against normal healthy tissues. Ellipticine, a chemotherapeutic agent, was loaded into the EGF-micelles after it had been shown, using the combination index-isobologram equation, to act synergistically with EGF. A 10-fold increase in EGF content in the ellipticine-loaded micelles lowered the IC 50 of ellipticine in EGFR-overexpressing breast cancer cells by more than 18-fold. The EGF-micelles have the potential to be further pursued as a versatile nanotechnology platform for targeted delivery of a wide range of chemotherapeutic agents as a combination therapy for the treatment of EGFR-overexpressing cancers.[1]References
- Apoptotic epidermal growth factor (EGF)-conjugated block copolymer micelles as a nanotechnology platform for targeted combination therapy. Lee, H., Hu, M., Reilly, R.M., Allen, C. Mol. Pharm. (2007) [Pubmed]
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