Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 8/2022

02-03-2022 | Prostate Cancer | Original Article

A self-triggered radioligand therapy agent for fluorescence imaging of the treatment response in prostate cancer

Authors: Hongchuang Xu, Yanpu Wang, Jingming Zhang, Xiaojiang Duan, Ting Zhang, Xuekang Cai, Hyunsoo Ha, Youngjoo Byun, Yan Fan, Zhi Yang, Yiguang Wang, Zhaofei Liu, Xing Yang

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 8/2022

Login to get access

Abstract

Purpose

Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT.

Methods

We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis.

Results

The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 μM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to 177Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model.

Conclusion

Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.
Appendix
Available only for authorised users
Literature
1.
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: global estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.PubMedCrossRef
2.
Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: a review. JAMA - J Am Med Assoc. 2017;317:2532–42.CrossRef
3.
4.
Hofman MS, Violet J, Hicks RJ, et al. [177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825–33.PubMedCrossRef
5.
6.
Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397:797–804.PubMedCrossRef
7.
Langbein T, Weber WA, Eiber M. Future of theranostics: an outlook on precision oncology in nuclear medicine. J Nucl Med. 2019;60:13S-S19.PubMedCrossRef
8.
Wüstemann T, Haberkorn U, Babich J, Mier W. Targeting prostate cancer: prostate-specific membrane antigen based diagnosis and therapy. Med Res Rev. 2019;39:40–69.PubMedCrossRef
9.
Fendler WP, Rahbar K, Herrmann K, Kratochwil C, Eiber M. 177Lu-PSMA radioligand therapy for prostate cancer. J Nucl Med. 2017;58:1196–200.PubMedCrossRef
10.
Gafita A, Heck MM, Rauscher I, et al. Early prostate-specific antigen changes and clinical outcome after 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer. J Nucl Med. 2020;61:1476–83.PubMedCrossRef
11.
Lee BS, Cho YW, Kim GC, et al. Induced phenotype targeted therapy: radiation-induced apoptosis-targeted chemotherapy. J Natl Cancer Inst. 2015;107:dju403.PubMed
12.
Fu Q, Li H, Duan D, et al. External-radiation-induced local hydroxylation enables remote release of functional molecules in tumors. Angew Chemie Int Ed Engl. 2020;59:21546–52.CrossRef
13.
14.
Paschalis A, Sheehan B, Riisnaes R, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur Urol. 2019;76:469–78.PubMedPubMedCentralCrossRef
15.
Zhang J, Chai X, He XP, Kim HJ, Yoon J, Tian H. Fluorogenic probes for disease-relevant enzymes. Chem Soc Rev. 2019;48:683–722.PubMedCrossRef
16.
Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.PubMedCrossRef
17.
18.
19.
He X, Hu Y, Shi W, Li X, Ma H. Design, synthesis and application of a near-infrared fluorescent probe for in vivo imaging of aminopeptidase N. Chem Commun. 2017;53:9438–41.CrossRef
20.
Yuan Y, Kwok RTK, Tang BZ, Liu B. Targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission light-up apoptosis sensor for noninvasive early evaluation of its therapeutic responses in situ. J Am Chem Soc. 2014;136:2546–54.PubMedCrossRef
21.
Zeng Z, Liew SS, Wei X, Pu K. Hemicyanine-based near-infrared activatable probes for imaging and diagnosis of diseases. Angew Chemie Int Ed Engl. 2021;60:2–24.CrossRef
22.
Yuan L, Lin W, Yang Y, Chen H. A unique class of near-infrared functional fluorescent dyes with carboxylic-acid-modulated fluorescence on/off switching: rational design, synthesis, optical properties, theoretical calculations, and applications for fluorescence imaging in living animals. J Am Chem Soc. 2012;134:1200–11.PubMedCrossRef
23.
Cheng D, Peng J, Lv Y, et al. De novo design of chemical stability near-infrared molecular probes for high-fidelity hepatotoxicity evaluation in vivo. J Am Chem Soc. 2019;141:6352–61.PubMedCrossRef
24.
Cheng P, Miao Q, Li J, Huang J, Xie C, Pu K. Unimolecular chemo-fluoro-luminescent reporter for crosstalk-free duplex imaging of hepatotoxicity. J Am Chem Soc. 2019;141:10581–4.PubMedCrossRef
25.
He X, Li L, Fang Y, Shi W, Li X, Ma H. In vivo imaging of leucine aminopeptidase activity in drug-induced liver injury and liver cancer via a near-infrared fluorescent probe. Chem Sci. 2017;8:3479–83.PubMedPubMedCentralCrossRef
26.
Tian X, Li Z, Ding N, Zhang J. Near-infrared ratiometric self-assembled theranostic nanoprobe: imaging and tracking cancer chemotherapy. Chem Commun. 2020;56:3629–32.CrossRef
27.
Rhéaume E, Cohen LY, Uhlmann F, et al. The large subunit of replication factor C is a substrate for caspase-3 in vitro and is cleaved by a caspase-3-like protease during fas-mediated apoptosis. EMBO J. 1997;16:6346–54.PubMedPubMedCentralCrossRef
28.
Kozikowski AP, Nan F, Conti P, et al. Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase). J Med Chem. 2001;44:298–301.PubMedCrossRef
29.
Yang X, Mease RC, Pullambhatla M, et al. Fluorobenzoyllysinepentanedioic acid carbamates: new scaffolds for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA). J Med Chem. 2016;59:206–18.PubMedCrossRef
30.
Duan X, Liu F, Kwon H, et al. (S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic acid as a novel PSMA targeting scaffold for prostate cancer imaging. J Med Chem. 2020;63:3563–76.PubMedCrossRef
31.
Müller C, Van Der Meulen NP, Benešová M, Schibli R. Therapeutic radiometals beyond 177Lu and 90Y: production and application of promising α-particle, β–particle, and auger electron emitters. J Nucl Med. 2017;58:91S-S96.PubMedCrossRef
32.
Benesová M, Schäfer M, Bauder-Wüst U, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med. 2015;56:914–20.PubMedCrossRef
33.
Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J Biol Chem. 1998;273:32608–13.PubMedCrossRef
34.
Choi B, Rempala GA, Kim JK. Beyond the Michaelis-Menten equation: accurate and efficient estimation of enzyme kinetic parameters. Sci Rep. 2017;7:17018. PubMedPubMedCentralCrossRef
35.
Chang Lee S, Ma JSY, Kim MS, et al. A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand. Sci Adv. 2021;7:eabi8193.CrossRef
36.
Kiess AP, Minn I, Chen Y, et al. Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen. J Nucl Med. 2015;56:1401–7.PubMedCrossRef
37.
Olszewski RT, Bukhari N, Zhou J, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem. 2004;89:876–85.PubMedCrossRef
38.
Cho YW, Kim SY, Kwon IC, Kim IS. Complex adaptive therapeutic strategy (CATS) for cancer. J Control Release. 2014;175:43–7.PubMedCrossRef
39.
Zhao Y, Zhang T, Wang YP, et al. ICAM-1 orchestrates the abscopal effect of tumor radiotherapy. Proc Natl Acad Sci USA. 2021;118:e2010333118.
40.
Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395:1208–16.PubMedCrossRef
41.
Eder M, Schäfer M, Bauder-Wüst U, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688–97.PubMedCrossRef
42.
Chen Y, Pullambhatla M, Foss CA, et al. 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]- pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res. 2011;17:7645–53.PubMedPubMedCentralCrossRef
43.
Zacherl MJ, Gildehaus FJ, Mittlmeier L, et al. First clinical results for PSMA-targeted α-therapy using 225Ac-PSMA-I&T in advanced-mCRPC patients. J Nucl Med. 2021;62:669–74.PubMedCrossRef
Metadata
Title
A self-triggered radioligand therapy agent for fluorescence imaging of the treatment response in prostate cancer
Authors
Hongchuang Xu
Yanpu Wang
Jingming Zhang
Xiaojiang Duan
Ting Zhang
Xuekang Cai
Hyunsoo Ha
Youngjoo Byun
Yan Fan
Zhi Yang
Yiguang Wang
Zhaofei Liu
Xing Yang
Publication date
02-03-2022
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 8/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-022-05743-7

Other articles of this Issue 8/2022

European Journal of Nuclear Medicine and Molecular Imaging 8/2022 Go to the issue

Original Article

P2X7 receptor-specific radioligand 18F-FTTM for atherosclerotic plaque PET imaging

Correction

Correction to: A pure nanoICG-based homogeneous lipiodol formulation: toward precise surgical navigation of primary liver cancer after long-term transcatheter arterial embolization

Review Article

Current status and future perspective of radiopharmaceuticals in China

Original Article

Fibroblast activation protein imaging in reperfused ST-elevation myocardial infarction: comparison with cardiac magnetic resonance imaging

Original Article

Size-changeable nanoprobes for the combined radiotherapy and photodynamic therapy of tumor

Original Article

Ultrafast 30-s total-body PET/CT scan: a preliminary study