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Review
. 2018 Feb 12;8(7):1824-1849.
doi: 10.7150/thno.22172. eCollection 2018.

Metal-based NanoEnhancers for Future Radiotherapy: Radiosensitizing and Synergistic Effects on Tumor Cells

Yan Liu  1   2   3   4 , Pengcheng Zhang  1   2   3   4 , Feifei Li  1   2   3   4 , Xiaodong Jin  1   2   3 , Jin Li  5 , Weiqiang Chen  1   2   3 , Qiang Li  1   2   3
Affiliations
Review

Metal-based NanoEnhancers for Future Radiotherapy: Radiosensitizing and Synergistic Effects on Tumor Cells

Yan Liu et al. Theranostics. .

Abstract

Radiotherapy is one of the major therapeutic strategies for cancer treatment. In the past decade, there has been growing interest in using high Z (atomic number) elements (materials) as radiosensitizers. New strategies in nanomedicine could help to improve cancer diagnosis and therapy at cellular and molecular levels. Metal-based nanoparticles usually exhibit chemical inertness in cellular and subcellular systems and may play a role in radiosensitization and synergistic cell-killing effects for radiation therapy. This review summarizes the efficacy of metal-based NanoEnhancers against cancers in both in vitro and in vivo systems for a range of ionizing radiations including gamma-rays, X-rays, and charged particles. The potential of translating preclinical studies on metal-based nanoparticles-enhanced radiation therapy into clinical practice is also discussed using examples of several metal-based NanoEnhancers (such as CYT-6091, AGuIX, and NBTXR3). Also, a few general examples of theranostic multimetallic nanocomposites are presented, and the related biological mechanisms are discussed.

Keywords: NanoEnhancers; metal-based nanoparticles; radiation therapy; radiosensitization; synergistic chemo-radiotherapy; tumor.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Potential radiosensitizers (red) and radioprotectors (green) that may be useful in modulating radiation effects. Reproduced with permission from reference , copyright 2013 American Association for the Advancement of Science.
Figure 2
Figure 2
Schematic illustration of metal-based NanoEnhancer radiosensitization process. (Upper-left) Following administration of NanoEnhancers, radiation therapy is carried out after a certain time interval. (Upper-right) Probable biological mechanisms include oxidative stress, cell cycle arrest, DNA repair inhibition, autophagy, ER stress, etc. Besides ionizing radiation-induced fluctuations in biological systems, the metal-based NanoEnhancers internalized by tumor cells can elicit significant cellular biochemical changes prior to, during, and following irradiation. (Lower-left) Classical radiosensitization process, which typically consists of physical dose enhancement, chemical contribution and biological phase, resulting in lethal cellular damage. The primary targets depending on cellular and subcellular distribution and location of metal-based NanoEnhancers include cell membrane, cytoplasm, nucleus, mitochondria, endoplasmic reticulum (ER), and other organelles. Specifically, photoelectrons and Auger electrons generated from the irradiated metal-based nanoparticles could contribute to the dose enhancement directly through the interactions with critical targets or indirectly through free radical production (mostly ROS (reactive oxygen species)), which can be assessed by DCFH-DA (2',7'-dichlorofluorescein diacetate) in living cell models and 3-CCA (coumarin-3-carboxylic acid) in aqueous buffered solutions. In addition, the production of hydroxyl radical in the radiosensitization processes of metal-based nanoparticles could be attributed to the catalytic-like mechanism/surface-catalyzed reaction (e.g., in IONs (iron oxide nanoparticles) this is the surface-catalyzed Haber-Weiss cycle and Fenton reaction). (Lower-right) Patterns of cell death in radiosensitization, such as apoptosis, necrosis, mitotic catastrophe, autophagic death, and senescence. Consequently, the enhanced cell-killing effects might result from the complicated physical, chemical and biological effects induced by the complex action of metal-based nanoparticles and ionizing radiation exposure.
Figure 3
Figure 3
(A-C) Radiation enhancement effect of gold nanoparticles (AuNPs) . (A) AuNPs improve the cell-killing effects of X-rays and fast carbon ions. (B) AuNPs improve the hydroxyl radical production of X-rays (assessed by 3-CCA). (C) AuNPs improve the hydroxyl radical production of carbon ions (assessed by 3-CCA). (D-E) Synergistic radiosensitizing effect of the reductive thioctyl tirapazamine (TPZs)-modified AuNPs (TPZs-AuNPs) . (D) The radiation enhancement mechanism of TPZs-AuNPs proposed in this study. (E) The fluorescence images of ROS with DCFH-DA in human hepatocellular carcinoma HepG2 cells after X-ray irradiation in the presence of TPZs-AuNPs. Scale bar = 200 μm. (F-G) Dynamically-enhanced retention of gold nanoclusters (AuNCs) in human cervical carcinoma HeLa cells following X-ray exposure . (F) Schematic illustration of our strategy for improving cellular uptake of nanoparticles. (G) The fluorescence intensities of cell samples after 24 h incubation with the as-prepared luminescent AuNCs used as both “nano-agents” and fluorescent trafficking probes (control and following 2.0 Gy X-ray irradiation). Reproduced with permission from references: , copyright 2015 Elsevier; , copyright 2016 Dove Medical Press; , copyright 2016 Elsevier.
Figure 4
Figure 4
Ultrasmall gadolinium-based nanoparticles (GdNPs) induce both a positive contrast for magnetic resonance imaging (MRI) and a radiosensitizing effect. (A) Transmission electron microscopy (TEM) phase-contrast imaging at low spatial resolution of Gd2O3 cores after encapsulation in a polysiloxane shell (insets show projected potential calculations of Gd2O3 after and before polysiloxane formation (top and bottom, respectively)). (B) MRI T1-weighted images of the brain of a 9L glioma-bearing rat before and after intravenous injection of GdNPs. (C) T1-weighted images of a slice including a kidney (K) and the bladder (B) of a rat before and after intravenous injection of GdNPs. (D) Synchrotron radiation computed tomography (SRCT) images of a series of successive transverse slices including the right and left kidneys (RK and LK, respectively) and the bladder (B) of a 9L glioma-bearing rat. The images were recorded before and after the intravenous injection of GdNPs. (E) Survival curve comparison obtained on 9L glioma-bearing rats without treatment (black dashed curve), only treated by microbeam radiation therapy (MRT)(blue curve), and treated by MRT 5 min (red curve) and 20 min (green curve) after GdNP intravenous injection during 103 days after tumor implantation. Reproduced with permission from reference , copyright 2011 American Chemical Society.
Figure 5
Figure 5
Tungsten sulfide (WS2) quantum dots (QDs) as multifunctional nanotheranostic agents for in vivo dual-modal image-guided photothermal/radiotherapy synergistic therapy. (A) Schematic illustration of WS2 QDs for dual-mode computed tomography (CT)/photoacoustic (PA) imaging and photothermal therapy (PTT)/radiation therapy (RT) synergistic therapy. (B) Atomic force microscopy (AFM) topography images of the as-prepared WS2 QDs. (C) Temperature change of WS2 QD solution at a concentration of 100 ppm over four laser on/off cycles. (D) PA images of BEL-7402 human hepatocellular carcinoma-bearing mice before and after the intravenous injection of WS2 QDs. (E) CT images of tumor before and after the intravenous injection of WS2 QDs. (F) Representative images of different groups of BEL-7402 human hepatocellular carcinoma-bearing mice after different administrations at the end of PTT and RT. Reproduced with permission from reference , copyright 2015 American Chemical Society.
Figure 6
Figure 6
Ultrasmall silica-based bismuth gadolinium nanoparticles (gadolinium-based AGuIX (Activation and Guidance of Irradiation by X-ray) nanoparticles with entrapped Bi (III)) for dual magnetic resonance/CT image-guided radiotherapy (IGRT). (A) These agents were synthesized by an original top-down process, which consists of Gd2O3 core formation, encapsulation by polysiloxane shell grafted with DOTAGA (1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid) ligands, Gd2O3 core dissolution following chelation of Gd (III) by DOTAGA ligands, and polysiloxane fragmentation. Moreover, at the final stage of the synthesis, DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid)-NHS (N-hydroxysuccinimide) ligands were grafted to the surface to entrap free Bi3+ atoms into the final complex. (B) MRI (relaxivity) and CT (Hounsfield units) linear relation with concentration of nanoparticles (metal) in aqueous solution. (C) Qualitative representation of γ-H2AX and 53BP1 (p53-binding protein 1) foci formation, with and without 4 Gy irradiation, with and without nanoparticles, 15 min post-irradiation. (D) Biodistribution study performed by ICP-MS (inductively coupled plasma-mass spectrometry) in animals after intravenous injection of nanoparticles. (E) Experimental timeline based on a current clinical workflow for MRI-guided radiotherapy. (F) Fusion of the CT and MRI images. Yellow arrows indicate the inceased contrast in the tumor. (G) Dosimetry study performed for a single fraction of 10 Gy irradiation delivered from a clinical linear accelerator (6 MV). (H) Dose-volume histogram showing the radiation dose distribution in the tumor and in the rest of the body. (I) Mean tumor volume of each group. (J) Overall survival of each treatment cohort. Reproduced with permission from reference , copyright 2017 American Chemical Society.
Figure 7
Figure 7
AuNPs induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment. (A) Effect of AuNPs on lysosome pH (representative fluorescence pictures of NRK cells (normal rat kidney) treated with AuNPs, then stained with LysoSensor Green DND-189 for evaluation of lysosomal acidity). Scale bar = 50 μm. (B) Vacuoles induced by AuNP treatment are enlarged lysosomes (inset: close-up of the enlarged lysosomes). Scale bar = 10 μm. (C) DQ-BSA (derivative-quenched bovine serum albumin, a self-quenched lysosome degradation indicator) analysis of lysosomal proteolytic activity. Accumulation of fluorescence signal, generated from lysosomal proteolysis of DQ-BSA, was much lower in AuNP-treated cells. Scale bar = 10 μm. (D) Formation of CFP (cyan fluorescent protein)-LC3 (microtubule-associated protein 1 light chain 3) dots (pseudocolored as green) in CFP-LC3 NRK cells treated with AuNPs. Left, confocal image; right, bright-field image. Scale bar = 10 μm. (E) LC3 turnover assay. The differences in LC3-I and LC3-II levels were compared by immunoblot analysis of cell lysates. (F) Degradation of the autophagy-specific substrate/polyubiquitin-binding protein p62/SQSTM1 (sequestosome 1) was detected by immunoblotting. Reproduced with permission from reference , copyright 2011 American Chemical Society.
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