Abstract
Epidermal growth factor receptor (EGFR) is associated with the progression of a wide range of cancers including breast, glioma, lung, and liver cancer. The observation that EGFR inhibition can limit the growth of EGFR positive cancers has led to the development of various EGFR inhibitors including monoclonal antibodies and small-molecule inhibitors. However, the reported toxicity and drug resistance greatly compromised the clinical outcome of such inhibitors. As a type of chemical antibodies, nucleic acid aptamer provides an opportunity to overcome the obstacles faced by current EGFR inhibitors. In this study, we have developed and investigated the therapeutic potential of a 27mer aptamer CL-4RNV616 containing 2′-O-Methyl RNA and DNA nucleotides. Our results showed that CL-4RNV616 not only displayed enhanced stability in human serum, but also effectively recognized and inhibited the proliferation of EGFR positive Huh-7 liver cancer, MDA-MB-231 breast cancer, and U87MG glioblastoma cells, with an IC50 value of 258.9 nM, 413.7 nM, and 567.9 nM, respectively. Furthermore, TUNEL apoptosis assay revealed that CL-4RNV616 efficiently induced apoptosis of cancer cells. In addition, clinical breast cancer biopsy-based immunostaining assay demonstrated that CL-4RNV616 had a comparable detection efficacy for EGFR positive breast cancer with commonly used commercial antibodies. Based on the results, we firmly believe that CL-4RNV616 could be useful in the development of targeted cancer therapeutics and diagnostics.
Highlights
The epidermal growth factor receptor (EGFR) is a subfamily of four closely related receptors including EGFR (ErbB-1), HER2/neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB-4) [1]
Various EGFR inhibitors [3], have been approved for cancer treatment. The application of these EGFR inhibitors has been compromised by toxicity and acquired drug resistance [4], which demonstrated the need for developing innovative therapeutic molecule capable of overcoming the challenges faced by existing EGFR inhibitors
Over the past decades, aptamer-based nanotechnology has been comprehensively investigated for biosensor development [9,10] and targeted therapeutics to deliver various types of cargoes ranging from small molecule drugs [11,12], nucleic acids [13] to nano-sized extracellular vesicles [14,15]
Summary
The epidermal growth factor receptor (EGFR) is a subfamily of four closely related receptors including EGFR (ErbB-1), HER2/neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB-4) [1]. Over the past decades, aptamer-based nanotechnology has been comprehensively investigated for biosensor development [9,10] and targeted therapeutics to deliver various types of cargoes ranging from small molecule drugs [11,12], nucleic acids [13] to nano-sized extracellular vesicles [14,15]. Generation of shorter aptamer sequences, in line with the FDA approved 27mer Macugen, could reduce the cost and toxicity. To address these limitations, we envisioned the development of a robust EGFR aptamer by rationale truncation and chemical modifications of the existing 39mer CL4 and extend its potential by evaluating in various cancer cells including malignant glioblastoma cells
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