Abstract
BackgroundThis study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR).MethodsMNTs are recombinant multifunctional polypeptides that we have developed for achieving selective delivery of short-range therapeutics into cancer cells. MNTs contain functional modules for receptor binding, internalization, endosomal escape and nuclear translocation, thereby facilitating the transport of drugs from the cell surface to the nucleus. The MNT described herein utilized EGF as the targeting ligand and was labeled with 125I using N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate (SGMIB). Membrane binding, intracellular and nuclear accumulation kinetics, and clonogenic survival assays were performed using the EGFR-expressing A431 epidermoid carcinoma and D247 MG glioma cell lines.Results[125I]SGMIB-MNT bound to A431 and D247 MG cells with an affinity comparable to that of native EGF. More than 60% of internalized [125I]SGMIB-MNT radioactivity accumulated in the cell nuclei after a 1-h incubation. The cytotoxic effectiveness of [125I]SGMIB-MNT compared with 125I-labeled bovine serum albumin control was enhanced by a factor of 60 for D247 MG cells and more than 1,000-fold for A431 cells, which express higher levels of EGFR.ConclusionsMNT can be utilized to deliver 125I into the nuclei of cancer cells overexpressing EGFR, significantly enhancing cytotoxicity. Further evaluation of [125I]SGMIB-MNT as a targeted radiotherapeutic for EGFR-expressing cancer cells appears warranted.
Highlights
This study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR)
The present study focuses on the development and the in vitro evaluation of a radiolabeled MNT possessing epidermal growth factor (EGF) as the ligand module, which might be suitable for targeting the many types of cancers overexpressing EGF receptors (EGFR) [8]
The binding affinity of [125I] SGMIB-MNT (Kd = 20.5 ± 2.6 nM), for EGFR measured on A431 cells was somewhat lower than that of [125I]
Summary
This study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR). We have demonstrated proof of principle for using MNT as a platform for developing targeted short-range (α-particle) radiotherapeutic agents for cancer therapy [7] Based on these encouraging results, we hypothesized that MNT might be a useful vehicle for exploiting the high potency and subcellular range of Auger electrons for targeted radiotherapy, enabling specific delivery of Auger electron-emitting radionuclides to the highly radiosensitive cell nucleus of cancer cells. The present study focuses on the development and the in vitro evaluation of a radiolabeled MNT possessing epidermal growth factor (EGF) as the ligand module, which might be suitable for targeting the many types of cancers overexpressing EGF receptors (EGFR) [8]. Internalization, nuclear translocation and cytotoxicity were evaluated using two EGFR-expressing human cancer cell lines - A431 epidermoid carcinoma cells and D247 MG malignant glioma cells, which express varying levels of EGFR
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