Radionuclide spatial distribution and dose deposition for in vitro assessments of ²¹²Pb‐αVCAM‐1 targeted alpha therapy

Abstract

Purpose Targeted alpha therapy (TAT) takes advantage of the short‐range and high‐linear energy transfer of α‐particles and is increasingly used, especially for the treatment of metastatic lesions. Nevertheless, dosimetry of α‐emitters is challenging for the very same reasons, even for in vitro experiments. Assumptions, such as the uniformity of the distribution of radionuclides in the culture medium, are commonly made, which could have a profound impact on dose calculations. In this study we measured the spatial distribution of α‐emitting 212Pb coupled to an anti‐VCAM‐1 antibody (212Pb‐αVCAM‐1) and its evolution over time in the context of in vitro irradiations. Methods Two experimental setups were implemented without cells to measure α‐particle count rates and energy spectra in culture medium containing 15 kBq of 212Pb‐α‐VCAM‐1. Silicon detectors were placed above and below cell culture dishes for 20 h. One of the dishes had a 2.5‐µm‐thick mylar‐base allowing easy detection of the α‐particles. Monte Carlo simulations were performed to analyze experimental spectra. Experimental setups were modeled and α‐energy spectra were simulated in the silicon detectors for different decay positions in the culture medium. Simulated spectra were then used to deconvolute experimental spectra to determine the spatial distribution of 212Pb‐αVCAM‐1 in the medium. This distribution was finally used to calculate the dose deposition in cell culture experiments. Results Experimental count rates and energy spectra showed differences in measurements taken at the top and the bottom of dishes and temporal variations that did not follow 212Pb decay. The radionuclide spatial distribution was shown to be composed of a uniform distribution and concentration gradients at the top and the bottom, which were subjected to temporal variations that may be explained by gravity and electrostatic attraction. The absorbed dose in cells calculated from this distribution was compared with the dose expected for a uniform and static distribution and found to be 1.75 times higher, which is highly significant to interpret biological observations. Conclusions This study demonstrated that accurate dosimetry of α‐emitters requires the experimental determination of radionuclide spatial and temporal distribution and highlighted that in vitro assessment of dose for TAT cannot only rely on a uniform distribution of activity in the culture medium. The reliability and reproducibility of future experiments should benefit from specifically developed dosimetry tools and methods.

Application of a new spectral deconvolution method for in vitro dosimetry in assessment of targeted alpha therapy

“…12,13 In this work, the radioisotopes' spatial and temporal distributions were determined using a silicon semiconductor spectrometer placed below the culture well. 11 This work confirmed the non-homogeneous distribution of the α-emitters within the well and the importance to use specific methods for this particular purpose. However, this previous deconvolution method required a quite long computing time not compatible with real-time dosimetry and allowed little flexibility on the deconvolution model.…”

“…The resolution of this equation guaranties an activity gradient toward the bottom of the well (observed in previous study 11 ) thanks to the k-th order derivation matrix D k that enforce monotony of the lower order derivatives of the solution. It also constrains the activity associated to the solution, equal to h T .a with h the vector of the elementary cylinders' heights, to be equal to the injected activity A 0 , using a penalty weight p. 𝚲 n is a weighting matrix enabling likelihood optimization.The definition of Equation ( 3) and its components are detailed in the Supplementary Materials.…”

“…The assumption of a homogeneous distribution of the radionuclides inside the well is most often done with limited consequences when β-emitters of longer ranges are considered, which is no longer the case with α-emitters. 11 Moreover, for a given dose delivered to the cells, the number of hits occurring during in vitro assays is way lower when α-particles are involved with respect to β-particles, the dose deposition from cell to cell thus becoming stochastic. 2,10 Due to geometrical effects, this stochasticity also highly depends on the spatial distribution of emissions.…”

The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

“…There are two radionuclides of bismuth with potential applications in a-therapy: 213 Bi (Ea( 213 Po) 8.4 MeV, gamma (g) 435 keV) and 212 Bi (Ea 8.8 and 6.1 MeV). [58,59] The particle energy released per disintegration of 213 Bi comprises 92.7 % from a and 7.3 % from beta-electron (b -) emission. Both 212 Bi and 213 Bi deliver high radiation doses within a short timeframe and have been investigated with large slower-circulating antibodies as well as small bioconjugates with rapid blood clearance.…”

Radioimmunotherapy for Brain Metastases: The Potential for Inflammation as a Target of Choice

“…In terms of tumour control, tumour volume and the number of BM were both decreased in comparison to the WBRT group, and the OS was significantly increased ( Figure 1 ). To understand the different therapeutic effects of 212 Pb-αVCAM-1 and WBRT, clonogenic assays were performed and showed higher radiosensitivity parameters, such as the survival fraction at 2 Gy or the dose that decreased the survival fraction by 50% ( 28 ), for 212 Pb-αVCAM-1 compared to WBRT. However, such an evaluation of radiosensitivity requires complex experiments with clonogenic assays that are not possible in clinical practice.…”