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Cytoplasmic localization of prostate-specific membrane antigen inhibitors may confer advantages for targeted cancer therapies

Graphical Abstract - <img class="highwire-fragment fragment-image" alt="Figure1" src="https://cancerres.aacrjournals.org/content/canres/81/8/2234/F1.medium.gif" width="440" height="307"/>Download figureOpen in new tabDownload powerpoint - - Ta...

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Main Authors: Matthias, Jessica (Author) , Engelhardt, Johann (Author) , Schäfer, Martin (Author) , Bauder-Wüst, Ulrike (Author) , Meyer, Philipp Tobias (Author) , Haberkorn, Uwe (Author) , Eder, Matthias (Author) , Kopka, Klaus (Author) , Hell, Stefan (Author) , Eder, Ann-Christin (Author)
Format: Article (Journal)
Language:English
Published: April 2021
In: Cancer research
Year: 2021, Volume: 81, Issue: 8, Pages: 2234-2245
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-20-1624
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-20-1624
Verlag, lizenzpflichtig, Volltext: https://cancerres.aacrjournals.org/content/81/8/2234
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Author Notes:Jessica Matthias, Johann Engelhardt, Martin Schäfer, Ulrike Bauder-Wüst, Philipp T. Meyer, Uwe Haberkorn, Matthias Eder, Klaus Kopka, Stefan W. Hell, and Ann-Christin Eder
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Summary:Graphical Abstract - <img class="highwire-fragment fragment-image" alt="Figure1" src="https://cancerres.aacrjournals.org/content/canres/81/8/2234/F1.medium.gif" width="440" height="307"/>Download figureOpen in new tabDownload powerpoint - - Targeted imaging and therapy approaches based on novel prostate-specific membrane antigen (PSMA) inhibitors have fundamentally changed the treatment regimen of prostate cancer. However, the exact mechanism of PSMA inhibitor internalization has not yet been studied, and the inhibitors' subcellular fate remains elusive. Here, we investigated the intracellular distribution of peptidomimetic PSMA inhibitors and of PSMA itself by stimulated emission depletion (STED) nanoscopy, applying a novel nonstandard live cell staining protocol. Imaging analysis confirmed PSMA cluster formation at the cell surface of prostate cancer cells and clathrin-dependent endocytosis of PSMA inhibitors. Following the endosomal pathway, PSMA inhibitors accumulated in prostate cancer cells at clinically relevant time points. In contrast with PSMA itself, PSMA inhibitors were found to eventually distribute homogeneously in the cytoplasm, a molecular condition that promises benefits for treatment as cytoplasmic and in particular perinuclear enrichment of the radionuclide carriers may better facilitate the radiation-mediated damage of cancerous cells. This study is the first to reveal the subcellular fate of PSMA/PSMA inhibitor complexes at the nanoscale and aims to inspire the development of new approaches in the field of prostate cancer research, diagnostics, and therapeutics. - Significance: This study uses STED fluorescence microscopy to reveal the subcellular fate of PSMA/PSMA inhibitor complexes near the molecular level, providing insights of great clinical interest and suggestive of advantageous targeted therapies. - Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/8/2234/F1.large.jpg.
Item Description:Gesehen am 23.07.2021
Physical Description:Online Resource
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-20-1624

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