Theranostic Gold Nanoparticles Modified for Durable Systemic Circulation Effectively and Safely Enhance the Radiation Therapy of Human Sarcoma Cells and Tumors

Abstract

Radiation therapy (RT) is an integral component of the treatment of many sarcomas and relies on accurate targeting of tumor tissue. Despite conventional treatment planning and RT, local failure rates of 10% to 28% at 5 years have been reported for locally advanced, unresectable sarcomas, due in part to limitations in the cumulative RT dose that may be safely delivered. We describe studies of the potential usefulness of gold nanoparticles modified for durable systemic circulation (through polyethylene glycosylation; hereinafter "P-GNPs") as adjuvants for RT of sarcomas. In studies of two human sarcoma-derived cell lines, P-GNP in conjunction with RT caused increased unrepaired DNA damage, reflected by approximately 1.61-fold increase in γ-H2AX (histone phosphorylated on Ser(139)) foci density compared with RT alone. The combined RT and P-GNP also led to significantly reduced clonogenic survival of tumor cells, compared to RT alone, with dose-enhancement ratios of 1.08 to 1.16. In mice engrafted with human sarcoma tumor cells, the P-GNP selectively accumulated in the tumor and enabled durable imaging, potentially aiding radiosensitization as well as treatment planning. Mice pretreated with P-GNP before targeted RT of their tumors exhibited significantly improved tumor regression and overall survival, with long-term survival in one third of mice in this treatment group compared to none with RT only. Interestingly, prior RT of sarcoma tumors increased subsequent extravasation and in-tumor deposition of P-GNP. These results together suggest P-GNP may be integrated into the RT of sarcomas, potentially improving target imaging and radiosensitization of tumor while minimizing dose to normal tissues.

Theranostic Application of Mixed Gold and Superparamagnetic Iron Oxide Nanoparticle Micelles in Glioblastoma Multiforme

“…After 24 hours, cells were fixed with 10% neutral buffered formalin (Sigma-Aldrich), nuclei were stained with Hoechst, slides were permeabilized with Triton-X, and cells were immunofluorescently stained for gh2ax as described previously. 36 Finally, fluorescence imaging on samples was performed using a Deltavision Deconvolution microscope (Applied Precision); and foci counting was accomplished using ImageJ as described previously. 36 …”

“…36 Finally, fluorescence imaging on samples was performed using a Deltavision Deconvolution microscope (Applied Precision); and foci counting was accomplished using ImageJ as described previously. 36 …”

Targeted nanoparticles for tumour radiotherapy enhancement—the long dawn of a golden era?

“…Electron-dense materials such as gold were proven to be suited for this purpose in a series of in vitro and in vivo studies [e.g., (10)(11)(12)(13)(14)(15)]. It is important to point out here that gold NP do not per se alter the cellular radiosensitivity of a tumour.…”

Metallic Nanoparticles, Toxicity Issues and Applications in Medicine

“…PEG-AuNPs in combination with radiotherapy have enhanced CT imaging whereas radiotherapy has helped to induce tumour tissue damage by increasing unrepaired DNA damage. This study has suggested that AuNPs can potentially improve target imaging and radiosensitization of tumour while minimizing dose to normal tissues thus providing more chances of survival to animals under experimentation (Joh et al 2013). Zhang et al (2015) have prepared high-density CuNPs which have provided fourfold higher signals as PAT contrast agents in NIR region than that of blood.…”