Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand 212Pb-NG001
by
, , ,
Vilde Yuli Stenberg
1,2,3,*,†
,
Anna Julie Kjøl Tornes
1,2,3,†,
Hogne Røed Nilsen
4,
Mona-Elisabeth Revheim
3,5,
Øyvind Sverre Bruland
3,6,
Roy Hartvig Larsen
2 and
Asta Juzeniene
1
1
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
2
Nucligen AS, 0379 Oslo, Norway
3
Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
4
Department of Pathology, Rikshospitalet, Oslo University Hospital, 0372 Oslo, Norway
5
Division of Radiology and Nuclear Medicine, Oslo University Hospital, 0379 Oslo, Norway
6
Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(11), 2784; https://doi.org/10.3390/cancers14112784
Submission received: 23 March 2022
/
Revised: 18 May 2022
/
Accepted: 1 June 2022
/
Published: 3 June 2022
(This article belongs to the Special Issue Prostate Cancer Therapy)
Simple Summary
Prostate-specific membrane antigen (PSMA) is a protein overexpressed in metastatic castration-resistant prostate cancer and a promising target for targeted radionuclide therapy. PSMA-targeted alpha therapy is of growing interest due to the high-emission energy and short range of alpha particles, resulting in a prominent cytotoxic potency. This study assesses the influence of various factors on the in vitro and in vivo therapeutic efficacy of the alpha particle generating PSMA-targeting radioligand 212Pb-NG001.
Abstract
This study aimed to determine the influence of cellular PSMA expression, radioligand binding and internalization, and repeated administrations on the therapeutic effects of the PSMA-targeting radioligand 212Pb-NG001. Cellular binding and internalization, cytotoxicity, biodistribution, and the therapeutic efficacy of 212Pb-NG001 were investigated in two human prostate cancer cell lines with different PSMA levels: C4-2 (PSMA+) and PC-3 PIP (PSMA+++). Despite 10-fold higher PSMA expression on PC-3 PIP cells, cytotoxicity and therapeutic efficacy of the radioligand was only 1.8-fold better than for the C4-2 model, possibly explained by lower cellular internalization and less blood-rich stroma in PC-3 PIP xenografts. Mice bearing subcutaneous PC-3 PIP xenografts were treated with 0.2, 0.4, and 0.8 MBq of 212Pb-NG001 that resulted in therapeutic indexes of 2.7, 3.0, and 3.5, respectively. A significant increase in treatment response was observed in mice that received repeated injections compared to the corresponding single dose (therapeutic indexes of 3.6 for 2 × 0.2 MBq and 4.4 for 2 × 0.4 MBq). The results indicate that 212Pb-NG001 can induce therapeutic effects at clinically transferrable doses, both in the C4-2 model that resembles solid tumors and micrometastases with natural PSMA expression and in the PC-3 PIP model that mimics poorly vascularized metastases.
