Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

Yvonne H W Derks; Melline G M Schilham; Mark Rijpkema; Esther M M Smeets; Helene I V Amatdjais-Groenen; Annemarie Kip; Sanne A M van Lith; Jill van de Kamp; J P Michiel Sedelaar; Diederik M Somford; Michiel Simons; Peter Laverman; Martin Gotthardt; Dennis W P M Löwik; Sandra Heskamp; Susanne Lütje

doi:10.1007/s00259-023-06224-1

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

Yvonne H W Derks^*, Melline G M Schilham, Mark Rijpkema, Esther M M Smeets, Helene I V Amatdjais-Groenen, Annemarie Kip, Sanne A M van Lith, Jill van de Kamp, J P Michiel Sedelaar, Diederik M Somford, Michiel Simons, Peter Laverman, Martin Gotthardt, Dennis W P M Löwik, Sandra Heskamp, Susanne Lütje

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.

METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.

RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).

CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

Original language	English
Pages (from-to)	2872-2884
Number of pages	13
Journal	European Journal of Nuclear Medicine and Molecular Imaging
Volume	50
Issue number	9
DOIs	https://doi.org/10.1007/s00259-023-06224-1
Publication status	Published - Apr 2023

Keywords

Intraoperative
PSMA ligands
Photodynamic therapy (PDT)
Prostate cancer
Prostate-specific membrane antigen (PSMA)
Theranostic agents

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Derks, Y. H. W., Schilham, M. G. M., Rijpkema, M., Smeets, E. M. M., Amatdjais-Groenen, H. I. V., Kip, A., van Lith, S. A. M., van de Kamp, J., Sedelaar, J. P. M., Somford, D. M., Simons, M., Laverman, P., Gotthardt, M., Löwik, D. W. P. M., Heskamp, S., & Lütje, S. (2023). Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand. European Journal of Nuclear Medicine and Molecular Imaging, 50(9), 2872-2884. https://doi.org/10.1007/s00259-023-06224-1

@article{b444592ad2fe45048233b78bba04179e,

title = "Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand",

abstract = "PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.",

keywords = "Intraoperative, PSMA ligands, Photodynamic therapy (PDT), Prostate cancer, Prostate-specific membrane antigen (PSMA), Theranostic agents",

author = "Derks, {Yvonne H W} and Schilham, {Melline G M} and Mark Rijpkema and Smeets, {Esther M M} and Amatdjais-Groenen, {Helene I V} and Annemarie Kip and {van Lith}, {Sanne A M} and {van de Kamp}, Jill and Sedelaar, {J P Michiel} and Somford, {Diederik M} and Michiel Simons and Peter Laverman and Martin Gotthardt and L{\"o}wik, {Dennis W P M} and Sandra Heskamp and Susanne L{\"u}tje",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = apr,

doi = "10.1007/s00259-023-06224-1",

language = "English",

volume = "50",

pages = "2872--2884",

journal = "European Journal of Nuclear Medicine and Molecular Imaging",

issn = "1619-7070",

publisher = "Springer-Verlag",

number = "9",

}

Derks, YHW, Schilham, MGM, Rijpkema, M, Smeets, EMM, Amatdjais-Groenen, HIV, Kip, A, van Lith, SAM, van de Kamp, J, Sedelaar, JPM, Somford, DM, Simons, M, Laverman, P, Gotthardt, M, Löwik, DWPM, Heskamp, S & Lütje, S 2023, 'Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand', European Journal of Nuclear Medicine and Molecular Imaging, vol. 50, no. 9, pp. 2872-2884. https://doi.org/10.1007/s00259-023-06224-1

TY - JOUR

T1 - Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

AU - Derks, Yvonne H W

AU - Schilham, Melline G M

AU - Rijpkema, Mark

AU - Smeets, Esther M M

AU - Amatdjais-Groenen, Helene I V

AU - Kip, Annemarie

AU - van Lith, Sanne A M

AU - van de Kamp, Jill

AU - Sedelaar, J P Michiel

AU - Somford, Diederik M

AU - Simons, Michiel

AU - Laverman, Peter

AU - Gotthardt, Martin

AU - Löwik, Dennis W P M

AU - Heskamp, Sandra

AU - Lütje, Susanne

PY - 2023/4

Y1 - 2023/4

N2 - PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

AB - PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

KW - Intraoperative

KW - PSMA ligands

KW - Photodynamic therapy (PDT)

KW - Prostate cancer

KW - Prostate-specific membrane antigen (PSMA)

KW - Theranostic agents

UR - http://www.scopus.com/inward/record.url?scp=85152406740&partnerID=8YFLogxK

U2 - 10.1007/s00259-023-06224-1

DO - 10.1007/s00259-023-06224-1

M3 - Article

C2 - 37060367

SN - 1619-7070

VL - 50

SP - 2872

EP - 2884

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

IS - 9

ER -

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

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