TY - JOUR
T1 - PSMA-targeted NIR probes for image-guided detection of prostate cancer
AU - Cilibrizzi, Agostino
AU - Wang, Julie Tzu Wen
AU - Memdouh, Siham
AU - Iacovone, Antonella
AU - McElroy, Kate
AU - Jaffar, Noor
AU - Young, Jennifer Denise
AU - Hider, Robert C.
AU - Blower, Philip
AU - Al-Jamal, Khuloud
AU - Abbate, Vincenzo
N1 - Funding Information:
This work was supported by the King’s Health Partners R&D Challenge Fund - MRC Confidence in concept (grant reference: MC_PC_17164 ). We are grateful to Theragnostics LTD for financial support to AC, JDY, RCH and VA. JDY was funded by the King’s College London and Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging ( EP/L015226/1 ). We are grateful to Dr Giuseppe Floresta and Dr Yu-Lin Chen for their assistance in the lab and fruitful discussions on the chemistry of this work.
Funding Information:
This work was supported by the King's Health Partners R&D Challenge Fund - MRC Confidence in concept (grant reference: MC_PC_17164). We are grateful to Theragnostics LTD for financial support to AC, JDY, RCH and VA. JDY was funded by the King's College London and Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1). We are grateful to Dr Giuseppe Floresta and Dr Yu-Lin Chen for their assistance in the lab and fruitful discussions on the chemistry of this work.
Publisher Copyright:
© 2022 The Authors
PY - 2022/10
Y1 - 2022/10
N2 - Tumour-targeted near-infrared (NIR) optical imaging is an emerging tool for the detection of malignant tissues. This modality can be useful in both diagnosis and intraoperative visualisation, to help defining tumour margins and allow a more precise removal of all the cancerous mass during surgery. In this context, we have developed a series of NIR fluorescent probes that target the prostate-specific membrane antigen (PSMA), an established biomarker overexpressed in prostate cancer. Four new NIR imaging agents were prepared by conjugating the well-known urea-based PSMA targeting module to the NIR fluorophore Cy7.5, with linkers of 7, 10, 17 and 24 atoms. The affinity of each probe for PSMA was assessed through competitive binding and IC50 measurement in prostate cancer cells, using a previously reported PSMA-targeted NIR probe (i.e. PSMA-IRDye800CW) as reference. The NIR probe PSMA-Cy7.5_2 demonstrated a high affinity for PSMA (i.e. IC50 = 58.8 nM) and was further studied in mouse xenograft models of prostate cancer, to assess its ability to image PSMA positive tumour tissues. While PSMA-Cy7.5_2 out-performed PSMA-IRDye800CW in vitro, its tumour accumulation in vivo was not as evident. Further micellar aggregation studies indicated that the relatively higher hydrophobic property of PSMA-Cy7.5_2 may lower its bioavailability and tissue distribution following systemic injection, limiting its ability of targeting PSMA tumour in vivo. Nevertheless, the excellent binding capability of PSMA-Cy7.5_2 renders this probe a valid lead for further structural optimisation to develop imaging analogues with high affinity and specificity for PSMA, as required for effective NIR fluorescence-guided applications pre-clinically and clinically.
AB - Tumour-targeted near-infrared (NIR) optical imaging is an emerging tool for the detection of malignant tissues. This modality can be useful in both diagnosis and intraoperative visualisation, to help defining tumour margins and allow a more precise removal of all the cancerous mass during surgery. In this context, we have developed a series of NIR fluorescent probes that target the prostate-specific membrane antigen (PSMA), an established biomarker overexpressed in prostate cancer. Four new NIR imaging agents were prepared by conjugating the well-known urea-based PSMA targeting module to the NIR fluorophore Cy7.5, with linkers of 7, 10, 17 and 24 atoms. The affinity of each probe for PSMA was assessed through competitive binding and IC50 measurement in prostate cancer cells, using a previously reported PSMA-targeted NIR probe (i.e. PSMA-IRDye800CW) as reference. The NIR probe PSMA-Cy7.5_2 demonstrated a high affinity for PSMA (i.e. IC50 = 58.8 nM) and was further studied in mouse xenograft models of prostate cancer, to assess its ability to image PSMA positive tumour tissues. While PSMA-Cy7.5_2 out-performed PSMA-IRDye800CW in vitro, its tumour accumulation in vivo was not as evident. Further micellar aggregation studies indicated that the relatively higher hydrophobic property of PSMA-Cy7.5_2 may lower its bioavailability and tissue distribution following systemic injection, limiting its ability of targeting PSMA tumour in vivo. Nevertheless, the excellent binding capability of PSMA-Cy7.5_2 renders this probe a valid lead for further structural optimisation to develop imaging analogues with high affinity and specificity for PSMA, as required for effective NIR fluorescence-guided applications pre-clinically and clinically.
KW - Image-guided detection
KW - in vivo imaging
KW - Near-infrared probes
KW - Optical imaging
KW - Prostate cancer
KW - Prostate-specific membrane antigen
UR - http://www.scopus.com/inward/record.url?scp=85135711841&partnerID=8YFLogxK
U2 - 10.1016/j.colsurfb.2022.112734
DO - 10.1016/j.colsurfb.2022.112734
M3 - Article
AN - SCOPUS:85135711841
SN - 0927-7765
VL - 218
JO - Colloids and Surfaces B: Biointerfaces
JF - Colloids and Surfaces B: Biointerfaces
M1 - 112734
ER -
