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Review
, 12 (2), 106-117

Utilizing the Power of Cerenkov Light With Nanotechnology

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Review

Utilizing the Power of Cerenkov Light With Nanotechnology

Travis M Shaffer et al. Nat Nanotechnol.

Abstract

The characteristic blue glow of Cerenkov luminescence (CL) arises from the interaction between a charged particle travelling faster than the phase velocity of light and a dielectric medium, such as water or tissue. As CL emanates from a variety of sources, such as cosmic events, particle accelerators, nuclear reactors and clinical radionuclides, it has been used in applications such as particle detection, dosimetry, and medical imaging and therapy. The combination of CL and nanoparticles for biomedicine has improved diagnosis and therapy, especially in oncological research. Although radioactive decay itself cannot be easily modulated, the associated CL can be through the use of nanoparticles, thus offering new applications in biomedical research. Advances in nanoparticles, metamaterials and photonic crystals have also yielded new behaviours of CL. Here, we review the physics behind Cerenkov luminescence and associated applications in biomedicine. We also show that by combining advances in nanotechnology and materials science with CL, new avenues for basic and applied sciences have opened.

Conflict of interest statement

Competing financial interests

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. The Cerenkov mechanism for blue-weighted luminescence
a, Top: A charged particle (red dot) travelling faster than light in a medium polarizes the medium. Bottom: As the medium returns to the ground state, blue-weighted light (blue wavy lines) is emitted in a forward direction. b, Analogous to a sonic boom, coherent waves are produced through the Cerenkov mechanism, leading to a photonic wavefront. As the particle travels forward (lower panel) the photonic wavefront propagates at a forward angle θ with light being emitted in the direction of travel. c, Cerenkov light is emitted (blue cone and arrow) by the medium in which a charged particle travels. Radionuclides that emit β-particles with energies greater than the Cerenkov threshold (261 keV in water) result in CL. d, In negative index materials, the cone of Cerenkov light is reversed compared with conventional materials, as in c.
Figure 2
Figure 2. Challenges of in vivo imaging of CL, highlighting the utility of photoluminescent nanoparticles
a, In vitro systems show the characteristic 1/λ2 spectrum as expected by the Frank–Tamm equation. Through the use of a calibrated preclinical optical scanner, a quantitative spectrum of CL from 100 µCi (3.7 MBq) of [18F]-FDG (red) or 89Zr (green) is obtained. b, When imaging CL in vivo, attenuation of higher-frequency photons is seen. Here, the CL spectrum from [18F]-FDG in the bladder of a mouse shows maximum intensities at wavelengths in the red–near-infrared region, whereas 89Zr in a matrigel plug closer to the surface has less attenuation of shorter-wavelength photons. The in vivo attenuation of the blue-weighted CL has led to the use of photoluminescent nanoparticles to address this shortcoming. Normalized radiance values (mean with s.d, n = 4) are shown.
Figure 3
Figure 3. Nanoparticle combinations with CL allow improved in vivo imaging
a, The three signals obtained from a CL–fluorescent nanoparticle (for example, QD) system: the blue CL, the red-shifted fluorescence and the PET signal, serving as an internal standard for quantification, make this a unique, truly multimodal quantitative system. High-energy electron–nanoparticle systems result in blue CL and redshifted fluorescence only. b, Three types of Cerenkov light–nanoparticle interactions: unbound Cerenkov emitters (left), surface-bound Cerenkov emitters (centre) and intrinsically self-illuminating crystals (right). Unbound Cerenkov emitters offer ease of translation through the possibility of using clinical radiotracers such as [18F]-FDG, but require co-location in space and time in vivo. Surface-bound Cerenkov emitters do not have the co-location limitation, but may result in possibly undesired signal from nonspecific distribution of the radiolabelled nanoparticle. Intrinsically self-illuminating particles offer superior in vivo stability, but the choice of nanoparticle–radionuclide system is limited by the possibility of lattice mismatch between the radionuclide and the nanoparticle elements.
Figure 4
Figure 4. Clinical small-molecule radiotracers and nanoparticles offer ease of clinical translation
a–d, IVIS optical images of QDs exhibiting SCIFI, where CL is shifted from blue light to more tissue-penetrating red light. Injection sites contain: 1, QD655/131I; 2, QD705/131I; 3, QD800/131I; 4, QD655/QD705/QD800/131I. All samples were injected intramuscularly with 0.37 MBq of 131I. a, QD655 filter (620–700 nm). b, QD705 filter (660–800 nm). c, QD 800 filter (760–840 nm). d, The spectral unmixed image of the same mouse, showing the different QD locations, represented by different colours. e–h, REFI demonstrates superior contrast compared with CLI and fluorescence molecular imaging (FMI). e, PET imaging showing equal 18F activity in each phantom. f,g, REFI and CLI of europium oxide nanoparticles with 18F show significant differences between no filtering (f) and a 620 nm filter (g). h, FMI of the in vivo phantom. Panels reproduced from ref. , Wiley (a–d) and ref. , Macmillan Publishers Ltd (e–h).
Figure 5
Figure 5. CL emitters can be incorporated into nanoparticles for high specific activity, multimodal probes
a, Different shaped gold nanostructures lead to differential biodistribution and tumour uptake. b, Autoradiographic images of tumour slices at 24 h post-injection of 198Au-incorporated gold nanospheres (NS), nanodiscs (ND), nanorods (NR) and cubic nanocages (CN). c, CL images of U87MG tumour-bearing mice at 6 h post-injection of 11.1 MBq of 64CuCl2, glutathione (GSH)-[64Cu]CIS/ZnS and PEGylated GSH-[64Cu]CIS/ZnS QDs, respectively, obtained with open and red filters (590 nm). The tumour is circled. d, Total photon flux in the corresponding tumour region obtained with open and red filters (*p < 0.05, n = 3, s.d. shown). e, The percentage of photon flux under a red filter in the total photon flux (*p < 0.05, n = 3, s.d shown). Panels reproduced from ref. , American Chemical Society (a,b) and ref. , American Chemical Society (c–e).
Figure 6
Figure 6. Smart, activatable nanoparticles allow in vivo modulation of radioactive signal along with therapeutic opportunities
a–d, CL for activatable imaging using radionuclides (n = 3, s.d. shown). a, Schematic of an enzyme-activatable SCIFI probe. Fluorescence is quenched when the fluorescein (FAM)-bearing peptide is bound to the surface of the gold nanoparticle. Enzymatic cleavage of the peptide by matrix metallopeptidase-2 (MMP-2) releases FAM, which is no longer quenched. IPVSLRSG is a peptide sequence cleaved by MMP-2 at the Ser-Leu bond, with [d] representing the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). b, Axial PET imaging of [18F]-FDG uptake in MMP-2–overexpressing xenografts (SCC7, +) and those with xenografts expressing a low level of MMP (BT20, –) showing a non-statistically significant (P > 0.2) difference in uptake. ID, injected dose. c, CLI of the Cerenkov signal recapitulates the PET readout of [18F]-FDG uptake. d, The activated probe can be visualized in the enzyme-expressing tumour through SCIFI using a filter for FAM, co-localizing enzyme and glycolytic activity. *P < 0.001. e–g, CL as a photon source in PDT. e, Cytotoxic radicals are generated in the presence of water and dissolved oxygen, from the interaction of CL with titanium dioxide nanoparticle (TiO2) through electron–hole pair generation. f, CL-mediated excitation of titanocene dichloride to generate additional radicals through photofragmentation. In aerated media, the radicals transform into more-potent peroxyl radicals. g, Top: Schematic illustrating the development of TiO2–PEG, TiO2–Tf (by coating TiO2 with transferrin, Tf) and the subsequent generation of the TiO2–Tf–Tc construct by the simple addition of titanocene dichloride (Tc), which docks into the iron-binding site of Tf (not to scale). Bottom (left to right): transmission electron microscopy images of TiO2–PEG, TiO2 aggregates, TiO2–Tf and TiO2–Tf–Tc. Scale bars, 50 nm. Panels reproduced from ref. , Nature America Inc. (a–d) and ref. , Macmillan Publishers Ltd (e–g).
Figure 7
Figure 7. The Cerenkov mechanism can be modified in unique ways through interaction with metamaterials and photonic crystals
a, The Vavilov-Cherenkov effect in a positive n (top) and a left-handed n (bottom) substance, where v is the particle velocity, k is the wavevector, S is the Poynting vector and θ is the cone angle formed. Traditional positive n material creates a forward facing Cherenkov cone with angle θ, while negative n material produces an obtuse cone, where the cone angles in the opposite direction to the particle velocity. b–e, Metamaterial examples utilizing CL in practice or conceived in theory. b, Copper split ring resonator with dimensions: ring width c = 0.8 mm, ring spacing d = 0.2 mm and inner radius r =1.5 mm. c, Diagram of Au–Si3N4–Ag waveguide ~500 nm in height for in-plane negative refraction, where t1, is the variable dielectric core thickness with edge angle θ, representing section W1 embedded in the waveguide of fixed core thickness t2 = 500 nm, representing section W2. d,e, Metamaterial structure 1 (d) and structure 2 (e) with periodic air slits in the metal denoted, g and p, where structure 2 introduces an additional periodicity with dimensions h′ and p′. Addition of periodicity amplifies the CL intensity produced in the far field (CL intensity profile right of structure design, denoted Ex) as represented by the energy density ripples at discrete angular frequencies ω. f, Top: finite-difference time-domain simulation results for CL in a photonic crystal. Each column represents the results for the value of velocity (v) shown on the top, where c is the speed of light in a vacuum. Overall radiation cone shapes (dashed lines) deduced from the group velocity contours where αm is the angle of the overall radiation cone. Bottom: distribution of the radiated magnetic field. Blue, white and red represent negative, zero and positive field values, respectively. The colours have been chosen separately for best illustration in each case. Panels reproduced from ref. , IOP (a), ref. , APS (b), ref. , AAAS (c), ref. , OSA (d,e) and ref. , AAAS (f).

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