Apoptotic Epidermal Growth Factor (EGF)-Conjugated Block Copolymer Micelles as a Nanotechnology Platform for Targeted Combination Therapy

详细信息    查看全文

• 作者：Helen Lee ; Meiduo Hu ; Raymond M. Reilly ; Christine Allen
• 刊名：Molecular Pharmaceutics
• 出版年：2007
• 出版时间：October 2007
• 年：2007
• 卷：4
• 期：5
• 页码：769 - 781
• 全文大小：929K
• 年卷期：v.4,no.5(October 2007)
• ISSN：1543-8392

文摘

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 G₁ 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 IC₅₀ 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 IC₅₀ 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.