Theranostics 2019; 9(10):2924-2938. doi:10.7150/thno.35274

Research Paper

Development and characterization of a theranostic multimodal anti-PSMA targeting agent for imaging, surgical guidance, and targeted photodynamic therapy of PSMA-expressing tumors

Susanne Lütje1,2,4, Sandra Heskamp1, Gerben M. Franssen1, Cathelijne Frielink1, Annemarie Kip1, Marlène Hekman1, Giulio Fracasso3, Marco Colombatti3, Ken Herrmann2, Otto C. Boerman1, Martin Gotthardt1, Mark Rijpkema1 ✉

1. Department of Radiology and Nuclear Medicine, Radboud university medical center, Nijmegen, the Netherlands
2. Clinic for Nuclear Medicine, University Hospital Essen, Germany
3. Department of Medicine, University of Verona, Verona, Italy
4. Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany

Abstract

Rationale: Prostate cancer (PCa) recurrences after surgery frequently occur. To improve the outcome after surgical resection of the tumor, the theranostic multimodal anti-PSMA targeting agent 111In-DTPA-D2B-IRDye700DX was developed and characterized for both pre- and intra-operative tumor localization and eradication of (residual) tumor tissue by PSMA-targeted photodynamic therapy (tPDT), which is a highly selective cancer treatment based on targeting molecules conjugated to photosensitizers that can induce cell destruction upon exposure to near-infrared (NIR) light.

Methods: The anti-PSMA monoclonal antibody D2B was conjugated with IRDye700DX and DTPA and subsequently radiolabeled with 111In. To determine the optimal dose and time point for tPDT, BALB/c nude mice with PSMA-expressing (PSMA+) s.c. LS174T-PSMA xenografts received the conjugate (24-240 µg/mouse) intravenously (8 MBq/mouse) followed by µSPECT/CT, near-infrared fluorescence imaging, and ex vivo biodistribution at 24, 48, 72 and 168 h p.i. Tumor growth of LS174T-PSMA xenografts and overall survival of mice treated with 1-3 times of NIR light irradiation (50, 100, 150 J/cm2) 24 h after injection of 80 µg of DTPA-D2B-IRDye700DX was compared to control conditions.

Results: Highest specific tumor uptake was observed at conjugate doses of 80 µg/mouse. Biodistribution revealed no significant difference in tumor uptake in mice at 24, 48, 72 and 168 h p.i. PSMA+ tumors were clearly visualized with both µSPECT/CT and NIR fluorescence imaging. Overall survival in mice treated with 80 µg of DTPA-D2B-IRDye700DX and 1x 150 J/cm2 of NIR light at 24 h p.i. was significantly improved compared to the control group receiving neither conjugate nor NIR light (73 days vs. 16 days, respectively, p=0.0453). Treatment with 3x 150 J/cm2 resulted in significantly prolonged survival compared to treatment with 3x 100 J/cm2 (p = 0.0067) and 3x 50 J/cm2 (p = 0.0338).

Principal conclusions: 111In-DTPA-D2B-IRDye700DX can be used for pre- and intra-operative detection of PSMA+ tumors with radionuclide and NIR fluorescence imaging and PSMA-targeted PDT. PSMA-tPDT using this multimodal agent resulted in significant prolongation of survival and shows great potential for treatment of (metastasized) prostate cancer.

Keywords: PSMA, prostate cancer, targeted photodynamic therapy, intra-operative, near-infrared fluorescence

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How to cite this article:
Lütje S, Heskamp S, Franssen GM, Frielink C, Kip A, Hekman M, Fracasso G, Colombatti M, Herrmann K, Boerman OC, Gotthardt M, Rijpkema M. Development and characterization of a theranostic multimodal anti-PSMA targeting agent for imaging, surgical guidance, and targeted photodynamic therapy of PSMA-expressing tumors. Theranostics 2019; 9(10):2924-2938. doi:10.7150/thno.35274. Available from http://www.thno.org/v09p2924.htm