Objectives: Targeted photodynamic therapy (tPDT) potentially is a highly selective cancer treatment based on targeting molecules conjugated to photosensitizers, which can induce cell destruction upon exposure to near-infrared (NIR) light. The aim of this study was to optimize the dose of 111In-DTPA-D2B-IRDye700DX for both pre- and intra-operative tumor localization as well as for eradication of tumor tissue by tPDT. Methods: The anti-PSMA mAb D2B was conjugated with DTPA and IRDye700DX (D2B:IRDye700DXratio 1:2.3) and subsequently radiolabeled with 111In. To determine the optimal time point for NIR light exposure, BALB/c nude mice with PSMA-expressing s.c. LS174T-PSMA xenografts received 30 µg of the conjugate intravenously (8 MBq/mouse) followed by µSPECT/CT, NIR fluorescence imaging, and biodistribution studies at 24, 48, 72, and 168 h p.i.. The optimal protein dose of the targeting agent was determined in mice with s.c. LS174T-PSMA xenografts that received 24, 80, or 240 µg of the conjugate i.v. (8 MBq/mouse) followed by µSPECT/CT, NIR fluorescence imaging, and biodistribution at 24 h p.i.. Tumor growth of 30 mice treated with 80 µg of the conjugate followed by 1, 5, or 15 min of NIR light irradiation at 24 h p.i. was compared to mice that did not receive any treatment. Results: 111In-DTPA-D2B-IRDye700DX specifically accumulated in the PSMA-expressing tumors. The protein dose escalation study revealed highest overall tumor accumulation in mice treated with 24 µg of the conjugate, reaching 32.7 ± 6.8% ID/g at 24 h p.i.. Highest specific tumor uptake was observed at antibody conjugate doses of 80 µg/mouse. The biodistribution studies revealed no significant differences in tumor uptake in mice treated with 30 µg of the conjugate at 24, 48, 72, and 168 h p.i.. PSMA+ tumors were clearly visualized with both µSPECT/CT and NIR fluorescence imaging. tPDT with 80 µg of the tracer and NIR light irradiation of 1, 5, and 15 min at 24 h p.i. caused modest tumor growth inhibition compared to non-treated tumors. Conclusion: 111In-DTPA-D2B-IRDye700DX can be used for pre- and intra-operative detection of PSMA+ tumors with radionuclide and fluorescence imaging as well as for PSMA-targeted PDT. A conjugate dose of 80µg/mouse results in high and specific tumor uptake and induces tumor growth inhibition upon NIR-light exposure.
|Titolo:||Characterization of an In-111-labeled anti-PSMA antibody-photosensitizer conjugate for targeted photodynamic therapy of PSMA-expressing tumors|
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||01.05 Abstract in rivista|