Radiosensitization of ultrasmall GNP–PEG–cRGDfK in ALTS1C1 exposed to therapeutic protons and kilovoltage and megavoltage photons

Abstract

Purpose: One of the promising radiosensitizers is the ultrasmall gold nanoparticle (GNP) with a hydrodynamic diameter <3 nm. We studied functionalized ultrasmall GNPs (1.8 nm diameter) coated by polyethylene glycol (PEG) and conjugated with cyclic RGDfK (2.6 nm hydrodynamic diameter) for targeting of alpha(v) beta(3) integrin (α_vβ₃) in the murine ALTS1C1 glioma cell line.

Materials and methods: We investigated the uptake, toxicity and radiosensitivity of GNP–PEG–cRGDfKs in ALTS1C1 cells exposed to protons, kilovoltage photons and megavoltage photons. The in vitro uptake and toxicity of GNPs in the hepatocytes and Kupffer cells were assessed for murine AML12 hepatocyte and RAW 264.7 macrophage cell lines. The in vivo biodistribution of GNPs in the ALTS1C1 tumor model was tested using the inductively coupled plasma mass spectrometry.

Results: Results indicated GNPs accumulated in the cytoplasm with negligible toxicity for a moderate concentration of GNPs. Observed sensitizer enhancement ratios and dose enhancement factors are 1.21–1.66 and 1.14–1.33, respectively, for all radiations.

Conclusion: Ultrasmall GNP–PEG–cRGD can be considered as a radiosensitizer. For radiotherapy applications, the delivery method should be developed to increase the GNP uptake in the tumor and decrease the uptakes in undesirable organs.

Keywords:

• GNP
• ALTS1C1
• cyclic RGD
• radiosensitization
• proton therapy

Acknowledgments

The authors gratefully acknowledge Dr. Yi-Hsiu Chung, Wen-Chi Chang (Center for Advanced Molecular Imaging and Translation (CAMIT), Chang Gung Memorial Hospital, Taoyuan, Taiwan) for help with intravenous (IV) injection, and Yi-Cheng Liu, Chi-Jung Wu, Hsiao-Chieh Huang, Xian-Xin Chen (Department of Radiation Oncology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan), Prof. Hui-Yu Tsai, Yu-Ying Lin (Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan), Cheng-Ya Pan, and Prof. Jian-Hao Zhu (Institute of Nuclear Energy Research, Longtan, Taiwan) for assistance with proton, MV and kV irradiations.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Notes on contributors

Milad Enferadi completed his Ph.D. in Medical Imaging and Radiological Sciences at Graduate Institute of Clinical Medical Sciences, Chang Gung University. This publication was in partial fulfillment of the requirements for a Ph.D. degree.

Sheng-Yung Fu is a PhD candidate at Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Taiwan. His research focuses on tumor microenvironment and radiation-induced immunological response, where he collaborated with Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou.

Ji-Hong Hong is a radiation oncologist and biologist. He is a professor at Chang Gung Memorial Hospital and Chang Gung University in Taiwan. His research interests are on normal tissue damage and changes of tumor microenvironment after high-dose irradiation. He has published many papers in these fields.

Chuan-Jong Tung is a distinguished professor and the Dean of Institute for Radiological Research at Chang Gung University in Taiwan. His recent research interests are in radiation dosimetry and microdosimetry for medical applications. He has published many papers in International Journal of Radiation Biology, Physics in Medicine and Biology, Medical Physics, Radiation Physics and Chemistry, and other journals.

Tsi-Chian Chao is an associate professor at the Department of Medical Imaging and Radiological Sciences, Chang Gung University (CGU), Taiwan. His research interests include Monte Carlo simulation and radiation dosimetry/instrumentation. Dr. Chao codirects the Radiation Therapy Laboratory at CGU, including responsibilities in quality assurance for radiation therapy, small field dosimetry, transmission dosimetry based on electronic portal imaging device, proton therapy, microdosimetry and nanodosimetry.

Shiaw-Pyng Wey is an adjunct associate professor at the Department of Medical Imaging and Radiological Sciences, Chang Gung University in Taiwan. His recent research interests include radiopharmaceutical chemistry, nuclear molecular imaging and PET drug cGMP. He has published many papers in International Journal of Radiation Biology, Journal of Nuclear Medicine, Annals of Nuclear Medicine, European Journal of Nuclear Medicine and Molecular Imaging, Nuclear Medicine and Biology, and other journals.

Chun-Hui Chiu is an assistant professor of Graduate Institute of Health-Industry Technology and QA supervisor of Food safety testing laboratory at Chang Gung University of Science and Technology in Taiwan. His recent research interests are the development and evaluation of testing methods for mass spectrometry.

Chun-Chieh Wang is an associate professor of the Institute for Radiological Research at Chang Gung University and a radiation oncologist at Chang Gung Memorial Hospital in Taiwan. His research interests are radiation effects on the stem cells and tumor microenvironments. Clinical specialties focus on brain tumor, lung cancer and Gyn cancer.

Mahdi Sadeghi is a professor at Iran University of Medical Science. His research interest is in Medical Radiation and Nuclear Medicine. He has over 15 years of experience in medical radioisotopes production that has led him to publish over 180 peer-reviewed publications.

Additional information

Funding

The project was supported by Ministry of Science and Technology, Taiwan and Chang Gung Memorial Hospital, LinKou, Taiwan [CMRPG3E1301&2, CIRPG3D0141 and CIRPD1E0053].