Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused\nradiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic\nradiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was\naimed to perform an initial dose-searching study for the combination of these treatment modalities\nin a preclinical setting. Therapy studies were performed with xenograft mouse models of folate\nreceptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors,\nrespectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either\nas single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar\ntumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either\nby protons or by Beta--particles, respectively. Combining the methodologies to provide half-dose by\neither therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy\noutcomes (KB tumor model). In separate experiments, preclinical positron emission tomography\n(PET) was performed to investigate tissue activation after proton irradiation of the tumor. The\nhigh-precision radiation delivery of PT was confirmed by the resulting PET images that accurately\nvisualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an\nadditive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study\nlaid the foundation for future research regarding therapy options in the situation of metastasized\nsolid tumors, where surgery or PT alone are not a solution but may profit from combination with\nsystemic radiation therapy.
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