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Open AccessArticle

Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute

1
Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
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Department of Chemistry and Applied Biosciences, ETH Zurich, 8092 Zurich, Switzerland
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Center for Proton Therapy, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
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Department of Radiation Physics, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
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Department of Medical Physics and Medical Bioengeneering, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden
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Laboratory of Radiochemistry, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
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Department of Radiation Oncology, University Hospital of Bern, 3010 Bern, Switzerland
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Department of Physics, ETH Zurich, 8093 Zurich, Switzerland
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(9), 450; https://doi.org/10.3390/pharmaceutics11090450
Received: 9 August 2019 / Revised: 23 August 2019 / Accepted: 26 August 2019 / Published: 2 September 2019
(This article belongs to the Special Issue Targeted Radionuclide Tumor Therapy)
Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy. View Full-Text
Keywords: proton therapy; targeted radionuclide therapy; PET imaging; folate receptor; PSMA; 177Lu; combination therapy proton therapy; targeted radionuclide therapy; PET imaging; folate receptor; PSMA; 177Lu; combination therapy
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    Description: Methods of cell culture, set-up of irradiation station, methods for preparation of the radioligands for TRT and PET/CT imaging; Figure S1: Chemical structures of the tumor targeting agents (folate and PSMA-617); Tables S1 and S2: previously-published biodistribution data of the radioligands; Figure S2: Sketch of the procedure of PET/CT imaging immediately after proton irradiation.
MDPI and ACS Style

Müller, C.; De Prado Leal, M.; Dominietto, M.D.; Umbricht, C.A.; Safai, S.; Perrin, R.L.; Egloff, M.; Bernhardt, P.; van der Meulen, N.P.; Weber, D.C.; Schibli, R.; Lomax, A.J. Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute. Pharmaceutics 2019, 11, 450. https://doi.org/10.3390/pharmaceutics11090450

AMA Style

Müller C, De Prado Leal M, Dominietto MD, Umbricht CA, Safai S, Perrin RL, Egloff M, Bernhardt P, van der Meulen NP, Weber DC, Schibli R, Lomax AJ. Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute. Pharmaceutics. 2019; 11(9):450. https://doi.org/10.3390/pharmaceutics11090450

Chicago/Turabian Style

Müller, Cristina; De Prado Leal, Maria; Dominietto, Marco D.; Umbricht, Christoph A.; Safai, Sairos; Perrin, Rosalind L.; Egloff, Martina; Bernhardt, Peter; van der Meulen, Nicholas P.; Weber, Damien C.; Schibli, Roger; Lomax, Antony J. 2019. "Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute" Pharmaceutics 11, no. 9: 450. https://doi.org/10.3390/pharmaceutics11090450

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