Noninvasive radiofrequency field-induced hyperthermic cytotoxicity in human cancer cells using cetuximab-targeted gold nanoparticles

Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Journal of Experimental Therapeutics and Oncology 02/2008; 7(4):313-26.
Source: PubMed

ABSTRACT Shortwave (MHz range) radiofrequency (RF) energy is nonionizing, penetrates deeply into biologic tissues with no adverse side effects, and heats gold nanoparticles efficiently. Targeted delivery of gold nanoparticles to cancer cells should result in hyperthermic cytotoxicity upon exposure to a focused, noninvasive RF field. In this report we demonstrate that gold nanoparticles conjugated with cetuximab (C225) are quickly internalized by Panc-1 (pancreatic adenocarcinoma) and Difi (colorectal adenocarcinoma) cancer cells overexpressing epidermal growth factor receptor (EGFR). Panc-1 or Difi cells treated with naked gold nanoparticles or nonspecific IgG-conjugated gold nanoparticles demonstrated minimal intracellular uptake of gold nanoparticles by transmission electron microscopy (TEM). In contrast, there were dense concentrations of cytoplasmic vesicles containing gold nanoparticles following treatment with cetuximab-conjugated gold nanoparticles. Exposure of cells to a noninvasive RF field produced nearly 100% cytotoxicity in cells treated with the cetuximab-conjugated gold nanoparticles, but significantly lower levels of cytotoxicity in the two control groups (P < 0.00012). Treatment of a breast cancer cell line (CAMA-1) that does not express EGFR with cetuximab-conjugated gold nanoparticles produced no enhanced cytotoxicity following treatment in the RF field. Conjugation of cancer cell-directed targeting agents to gold nanoparticles may represent an effective and cancer-specific therapy to treat numerous types of human malignant disease using noninvasive RF hyperthermia.

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    • "This is not the case at NIR, where all such macroscale samples are electrically large and usually a collimated beam is applied to a small area of the sample. Absorption of RF energy by solutions of spherical nanoparticles has been of considerable recent interest [6]–[14]. However, for spherical nanoparticles, low-frequency absorption of energy is predicted to be very small, and it has recently been shown both experimentally and theoretically that spherical gold nanoparticles in colloidal solutions are themselves minimally heating at RF [15]–[18]. "
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    ABSTRACT: Electromagnetic absorption and subsequent heating of nanoparticle solutions and simple NaCl ionic solutions is examined for biomedical applications in the radiofrequency range at 13.56 MHz. It is shown via both theory and experiment that for in vitro measurements the shape of the solution container plays a major role in absorption and heating.
    IEEE transactions on bio-medical engineering 09/2012; 59(12). DOI:10.1109/TBME.2012.2219049 · 2.35 Impact Factor
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    • "The concept goes a step further from traditional RF-hyperthermia by incorporating metal ions or metal particles to enhance heating in localized regions as compared to surrounding regions, where enhancers are not present. Initial studies demonstrated that low concentrations of conductive nanoparticles consisting of gold nanospheres [21] or carbon nanotubes [17] cause dramatically increased absorption of RF-EM energy, which is then dissipated in the form of heat. It has also been demonstrated that metal ion solutions produce a similar effect [18]. "
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    ABSTRACT: Gold nanoparticles (GNPs) are nontoxic, can be functionalized with ligands, and preferentially accumulate in tumors. We have developed a 13.56-MHz RF-electromagnetic field (RFEM) delivery system capable of generating high E-fleld strengths required for noninvasive, noncontact heating of GNPs. The bulk heating and specific heating rates were measured as a function of NP size and concentration. It was found that heating is both size and concentration dependent, with 5 nm particles producing a 50.6 ± 0.2°C temperature rise in 30 s for 25 μg/mL gold (125 W input). The specific heating rate was also size and concentration dependent, with 5 nm particles producing a specific heating rate of 356 ± 78 kW/g gold at 16 μg/mL (125 W input). Furthermore, we demonstrate that cancer cells incubated with GNPs are killed when exposed to 13.56 MHz RF-EM fields. Compared to cells that were not incubated with GNPs, three out of four RF-treated groups showed a significant enhancement of cell death with GNPs (p <; 0.05). GNP-enhanced cell killing appears to require temperatures above 50°C for the experimental parameters used in this study. Transmission electron micrographs show extensive vacuolization with the combination of GNPs and RF treatment.
    IEEE Transactions on Biomedical Engineering 08/2011; 58(7-58):2002 - 2012. DOI:10.1109/TBME.2011.2124460 · 2.35 Impact Factor
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    • "Non-invasive radiofrequency-based hyperthermia, unlike radiofrequency ablation, requires an external radiofrequency field generator (Kanzius RF generator) [14, 22, 23]. This is a variable power (0–2 KW) 13.56 MHz RF field generator (Therm Med LLC, Erie, Pennsylvania). "
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    ABSTRACT: Targeted biological therapies for hepatocellular cancer have shown minimal improvements in median survival. Multiple pathways to oncogenesis leading to rapid development of resistance to such therapies is a concern. Non-invasive radiofrequency field-induced targeted hyperthermia using nanoparticles is a radical departure from conventional modalities. In this paper we underscore the need for innovative strategies for the treatment of hepatocellular cancer, describe the central paradigm of targeted hyperthermia using non-invasive electromagnetic energy, review the process of characterization and modification of nanoparticles for the task, and summarize data from cell-based and animal-based models of hepatocellular cancer treated with non-invasive RF energy. Finally, future strategies and challenges in bringing this modality from bench to clinic are discussed.
    05/2011; 2011(3):676957. DOI:10.4061/2011/676957
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