Radio-enhancement effects by radiolabeled nanoparticles

In cancer radiation therapy, dose enhancement by nanoparticles has to date been investigated only for external beam radiotherapy (EBRT). Here, we report on an in silico study of nanoparticle-enhanced radiation damage in the context of internal radionuclide therapy. We demonstrate the proof-of-principle that clinically relevant radiotherapeutic isotopes (i.e. 213Bi, 223Ra, 90Y, 177Lu, 67Cu, 64Cu and 89Zr) labeled to clinically relevant superparamagnetic iron oxide nanoparticles results in enhanced radiation damage effects localized to sub-micron scales. We find that radiation dose can be enhanced by up to 20%, vastly outperforming nanoparticle dose enhancement in conventional EBRT. Our results demonstrate that in addition to the favorable spectral characteristics of the isotopes and their proximity to the nanoparticles, clustering of the nanoparticles results in a nonlinear collective effect that amplifies nanoscale radiation damage effects by electron-mediated inter-nanoparticle interactions. In this way, optimal radio-enhancement is achieved when the inter-nanoparticle distance is less than the mean range of the secondary electrons. For the radioisotopes studied here, this corresponds to inter-nanoparticle distances <50 nm, with the strongest effects within 20 nm. The results of this study suggest that radiolabeled nanoparticles offer a novel and potentially highly effective platform for developing next-generation theranostic strategies for cancer medicine.

For each GEANT4 simulation 10 6 decays of the above unstable nuclei was simulated in an otherwise empty geometry. Also, any subsequent unstable daughter nuclei were allowed for further decay. The energy spectrum of radiation and particles resulting from the decay of each isotope was recorded separately for each radiation type (e.g. α, " , ) into different histograms. In addition, for 64 Cu isotope, the GEANT4 the radioactive decay model was further modified to obtain separate " and # energy spectra. The maximum energies of the emitted " and # particles (which are equivalent to Q, the total kinetic energy released per decay) were compared against the analytical calculations for validation. Equation 1 and 2 were used to calculate the maximum energies for β + and βparticles: Where ' ( and ' E are the total kinetic energy released from # and " decay processes, respectively. and 5 are also the atomic number and the rest mass of the electron, respectively. -.

The computed spectra for all isotopes
Radioactive decay was simulated differently depending on the type of radiation emitted by the radioisotope. For 223 Ra and 213 Bi isotopes, which are -emitters, a He-nucleus was emitted from the parent nucleus resulting in daughter nuclei with two fewer protons and two fewer neutrons than the parent nuclei. The parent and daughter nuclei can subsequently undergo " decay, which produces a continuous energy spectrum. De-excitation by emission may also occur. Figure. 1(a-b) presents the energy spectra for , " and emissions for the full decay scheme of 213 Bi and 223 Ra radioisotopes, respectively. The intensity is weighted relative to the total energy released per decay. The full decay scheme for each isotope is presented in Fig. 2 and 3, respectively.
177 Lu and 67 Cu are primarily " emitters, but also have a decay branch. The full decay spectra additionally include the emission of conversion electron (CE) and Auger electrons (AE). The energy spectra of " particles, , CEs and AEs from 177 Lu and 67 Cu decays are shown in Fig. 4 (a-b). The full decay scheme for each isotope is presented in Fig. 5 and 6, respectively.
The full 64 Cu and 89 Zr decay scheme includes " , # and emission, as well as AE emission. The 89 Zr # , 64 Cu " and # energy spectra are shown in Fig. 7(a-b). The differences in the 64 Cu " and # energy spectrum shapes at low energies is due to differences in the electronnuclear and positron-nuclear Coulomb interactions, as a result of their opposite charges. The proportion of low-energy " particles exceeds that of low-energy positrons due to the nuclear Coulomb attraction and repulsion, respectively. Additionally, the analytical calculations (using Eq. (1) and (2)) for maximum energies of β − and β + particles were 0.578 MeV and 0.653 MeV, respectively. These results are also consistent with the computed maximum energies and previously published data 2 (i.e. 0.577 MeV and 0.654 MeV, respectively). The full decay scheme for 64 Cu and 89 Zr presented in Fig. 8 and 9, respectively.
Figure 7(c) shows the emission spectrum for, 90 Y, which primarily decays via β − decay (99.999%) 3 . However, the decay of 90 Y has a minor branch (0.011%) to the 0 + , first excited state of 90 Zr at 1.76 MeV, which is followed by a " / # emission 4 . Single gamma emission is strictly forbidden for spin-zero to spin-zero transitions. Thus, a possible process that could occur is the transitions giving rise to transfer of radiation energy to an atomic electron in the orbital cloud by internal conversion. If the energy of the process is greater than 2mec (1.022 MeV, where me is the rest mass of the electron), transition can occur via electron-positron internal pair creation 3 . This internal pair production is generated by a rare electric monopole transition (E0) between the states 0+/0+ of 90 Zr. Since the # emission yield from 90 Y decay is insignificant it was not included in the spectrum plot. The full decay scheme is presented in Fig. 10.          Tables Table 1. Total number of disintegrations for 1 kBq activity with relative particle intensities. The intensity for each type of radiation is weighted relative to the total energy released per decay. Abbreviations: alpha particle, ; beta particle " ; positron # , gamma , Auger electron and conversion electron, AE and CE, respectively.