UV emitting nanoparticles enhance the effect of ionizing radiation in 3D lung cancer spheroids

Abstract

Purpose

Radiation therapy for cancer is limited by damage to surrounding normal tissues, and failure to completely eradicate a tumor. This study investigated a novel radiosensitizer, composed of lutetium phosphate nanoparticles doped with 1% praseodymium and 1.5% neodymium cations (LuPO₄:Pr³⁺,Nd³⁺). During X-ray exposure, the particles emit UVC photons (200–280 nm), resulting in increased tumor cell death, by oxygen-independent UVC-induced damage.

Methods and Materials

Specially designed LuPO₄:Pr³⁺,Nd³⁺ nanoscintillator particles were characterized by dynamic light scattering, TEM and emission spectroscopy upon excitation. Cell death was determined by reduction in tumor spheroid growth over a 3-week period using a 3 D A549 lung cancer model. Cell cycle was evaluated by flow cytometry and cell death pathways were assessed by Annexin V/PI stain as well as quantify apoptotic bodies.

Results

Lung cancer cells expressed no long-term or nonspecific toxicity when incubated with LuPO₄:Pr³⁺,Nd³⁺ nanoscintillators. In contrast, there was significant growth inhibition of cell spheres treated with 2.5 mg/ml LuPO₄:Pr³⁺,Nd³⁺ in combination with ionizing radiation (4 or 8 Gy X-ray), compared to radiation alone. Homogeneous distribution of small NPs throughout the entire sphere resulted in more pronounced lethality and growth inhibition, compared to particle distribution limited to the outer cell layers. Growth inhibition after the combined treatment was caused by necrosis, apoptosis and G₂/M cell cycle arrest.

Conclusions

Newly designed UVC-emitting nanoscintillators (LuPO₄:Pr³⁺,Nd³⁺) in combination with ionizing radiation cause tumorsphere growth inhibition by inducing cell cycle arrest, apoptosis and necrosis. UVC-emitting nanoparticles offer a promising new strategy for enhancing local tumor response to ionizing radiation treatment.

Graphical abstract text

Our group has developed a new nanosized UVC emitting radiosensitizer to significantly enhance the biological effect of ionizing radiation. The nanoparticles absorb X-rays and convert them into lower energetic UVC photons (200–280 nm) which results in DNA damage, cell cycle arrest, and ultimately cell death. The combined treatment caused a significant size decrease of 3 D lung cancer spheroids.

Keywords:

• 3D cancer spheroids
• UVC emitting nanoparticles
• X-irradiation
• hypoxia
• apoptosis
• cell cycle arrest
• nanoparticle uptake

Acknowledgements

The authors would like to thank Jie Zhao and Neema Devi Kumar for TEM pictures, Matthias Mueller for helping in setting up the nanoparticles and cell culture experiments, as well as Anjan Motamarry for his fruitful discussions.

Disclosure statement

We have no conflicts of interest to disclose.

Additional information

Funding

This research is sponsored by the National Cancer Institute of the National Institutes of Health (NIH) under award number 1R41CA206645-01A1 and the Wellman Center for Photomedicine Early Discovery Fund and in part by Lancer Endowed Chair funding (RRA).

Notes on contributors

Thao Anh Tran

Thao Anh Tran, PhD, is a Research Fellow of Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Jan Kappelhoff

Jan Kappelhoff, MS, is a PhD student of Inorganic Chemistry and Material Sciences, Münster University of Applied Sciences, Münster, Germany.

Thomas Jüstel

Thomas Jüstel, PhD, is a Professor of Inorganic Chemistry and Material Sciences, Münster University of Applied Sciences, Münster, Germany.

R. Rox Anderson

Rox Anderson, MD, PhD, is a Professor of Harvard Medical School and a Director of Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Martin Purschke

Martin Purschke, PhD, is an Instructor – Senior Research Fellow of Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.