Call to arms: need for radiobiology in molecular radionuclide therapy

International audienc

Targeting Micrometastases:The Effect of Heterogeneous Radionuclide Distribution on Tumor Control Probability

The spatial distribution of radiopharmaceuticals that emit short-range high linear-energy-transfer electrons greatly affects absorbed dose and biological effectiveness. The purpose of this study was to investigate the effect of heterogeneous radionuclide distribution on tumor control probability (TCP) in a micrometastasis model. Methods: The cancer cell lines MDA-MB-468, SQ20B, and 231-H2N were grown as spheroids to represent micrometastases. The intracellular distribution of a representative radiopeptide (111In-labeled epidermal growth factor) and radioimmunotherapeutic (111In-labeled trastuzumab) was determined in cell internalization experiments. The intratumoral distribution was evaluated by microautoradiography of spheroids. γH2AX staining was performed on spheroid sections to correlate DNA damage with radionuclide distribution. Experimental surviving fractions were obtained using clonogenic assays. A random close-packed algorithm, which models the random packing behavior of cells and reflects variation in the radii of cells and nuclei, was used to simulate 3-dimensional spheroids. Calculated survival fractions were generated using an iterative modeling method based on Monte Carlo–determined absorbed dose with the PENELOPE code and were compared with experimental surviving fraction. Radiobiologic parameters deduced from experimental results and Monte Carlo simulations were used to predict the TCP for a 3-dimensional spheroid model. Results: Calculated survival fractions agreed well with experimental data, particularly when an increased value for relative biological effectiveness was applied to self-dose deposited by sources located in the nucleus and when radiobiologic parameters were adjusted to account for dose protraction. Only in MDA-MB-468 spheroids treated with 111In-epidermal growth factor was a TCP of more than 0.5 achieved, indicating that for this cell type the radiopeptide would be curative when targeting micrometastases. This ability is attributed to the relative radiosensitivity of MDA-MB-468 cells, high nuclear uptake of the radiopeptide, and uniform distribution of radioactivity throughout the spheroid. Conclusion: It is imperative to include biologic endpoints when evaluating the distribution of radionuclides in models emulating micrometastatic disease. The spatial distribution of radioactivity is a clear determinant of biological effect and TCP as demonstrated in this study

In vivo imaging of antileukemic drug asparaginase reveals a rapid macrophage mediated clearance from the bone marrow

Contains fulltext : 170243.pdf (publisher's version ) (Closed access)The antileukemic drug asparaginase, a key component in the treatment of acute lymphoblastic leukemia, acts by depleting asparagine from the blood. However, little is known about its pharmacokinetics, and mechanisms of therapy resistance are poorly understood. Here, we explored the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochemical techniques, and provide evidence for tissue-specific clearance mechanisms, which could reduce the effectiveness of the drug at these specific sites. METHODS: In vivo localization of 111In-labeled Escherichia coli asparaginase was performed in C57BL/6 mice by both small-animal SPECT/CT and ex vivo biodistribution studies. Mice were treated with liposomal clodronate to investigate the effect of macrophage depletion on tracer localization and drug clearance in vivo. Moreover, macrophage cell line models RAW264.7 and THP-1, as well as knockout mice, were used to identify the cellular and molecular components controlling asparaginase pharmacokinetics. RESULTS: In vivo imaging and biodistribution studies showed a rapid accumulation of asparaginase in macrophage-rich tissues such as the liver, spleen, and in particular bone marrow. Clodronate-mediated depletion of phagocytic cells markedly prolonged the serum half-life of asparaginase in vivo and decreased drug uptake in these macrophage-rich organs. Immunohistochemistry and in vitro binding assays confirmed the involvement of macrophagelike cells in the uptake of asparaginase. We identified the activity of the lysosomal protease cathepsin B in macrophages as a rate-limiting factor in degrading asparaginase both in vitro and in vivo. CONCLUSION: We showed that asparaginase is rapidly cleared from the serum by liver-, spleen-, and bone marrow-resident phagocytic cells. As a consequence of this efficient uptake and protease-mediated degradation, particularly bone marrow-resident macrophages may provide a protective niche to leukemic cells