PSMA-targeting agents for radio- and fluorescence-guided prostate cancer surgery

Abstract

Despite recent improvements in imaging and therapy, prostate cancer (PCa) still causes substantial morbidity and mortality. In surgical treatment, incomplete resection of PCa and understaging of possible undetected metastases may lead to disease recurrence and consequently poor patient outcome. To increase the chance of accurate staging and subsequently complete removal of all cancerous tissue, prostate specific membrane antigen (PSMA) targeting agents may provide the surgeon an aid for the intraoperative detection and resection of PCa lesions. Two modalities suitable for this purpose are radionuclide detection, which allows sensitive intraoperative localization of tumor lesions with a gamma probe, and fluorescence imaging, allowing tumor visualization and delineation. Next to fluorescence, use of photosensitizers may enable intraoperative targeted photodynamic therapy to eradicate remaining tumor lesions. Since radiodetection and optical imaging techniques each have their own strengths and weaknesses, a combination of both modalities could be of additional value. Here, we provide an overview of recent preclinical and clinical advances in PSMA-targeted radio- and fluorescence-guided surgery of PCa.

Keywords: PSMA; fluorescence; image-guided surgery; multimodal imaging.; radionuclide.

Figure 1

Chemical structures of [¹¹¹In]In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE) (PSMA-I&T) and [^99mTc]Tc-mas3-y-nal-k(Sub-KuE) (PSMA-I&S).

Figure 2

Preoperative imaging using ⁶⁸Ga-PSMA-11 PET/CT 1 h p.i. (A) and ¹¹¹In-PSMA-I&T SPECT/CT and planar scintigraphy (4 h p.i., 155 MBq) (B). Axial ⁶⁸Ga-PSMA-11 PET/CT images of the primary tumor in the prostate (D) and a representative lymph node (G). Corresponding CT images (C, F) and axial ¹¹¹In-PSMA-I&T SPECT/CT images (E, H). H&E staining (I) and ¹¹¹In-autoradiography (J) of cryosections from resected prostate tissue. The human study was approved by the institutional review boards of the participating medical institutions, and the patient provided signed informed consent. Reprinted with permission from Schottelius et al., ¹¹¹In-PSMA-I&T: expanding the spectrum of PSMA-I&T applications towards SPECT and radioguided surgery, Copyright 2015, Springer .

Figure 3

(A) Chemical structure of PSMA-binding motifs GPI [1], glutamate-urea-lysine (KuE) [2], PSMA-1 [3], DUPA [4], and YC27 [5]. (B) Chemical structures of fluorescent dyes IRDye78 [6], ZW800+3C [7], Cy5.5 [8], SO456 [9], IRDye800CW [10], IRDye700DX [11].

Figure 4

Sequential tumor debulking surgery and H&E analysis of 22RV1 tumor metastases 4 h p.i. with DUPA-IRDye800CW (10 nmol). Fluorescent and white light image overlays of whole body image (A), opened chest cavity (B), after the removal of the primary tumor (blue arrow) (C) and after the removal of all secondary nodules (purple arrow) (D). H&E staining healthy control lung (a), primary tumor (b), secondary tumor nodule (c) and residual tissue (d). Reprinted with permission from Kelderhouse et al., Development of tumor-targeted near infrared probes for fluorescence guided surgery, Copyright 2013, American Chemical Society .

Figure 5

Schematic representation of multimodal radio- and fluorescence-guided surgery. PK: pharmacokinetics

Figure 6

Proof-of-principle fluorescence-guided surgery studies with multimodal ⁶⁸Ga-IRDye800CW-PSMA-11 in tumor-bearing mice and healthy pigs. (A) ⁶⁸Ga-IRDye800CW-PSMA-11 (0.5 nmol) was injected in s.c. LNCaP tumor-bearing mice for small-animal PET imaging, followed by ex vivo fluorescence detection 2 h p.i. (IMAGE1 S system). (B) After preimaging acquisition of background fluorescence (da Vinci FireFly system), IRDye800CW-PSMA-11 (30 μg/kg) was injected i.v. in healthy pigs. 1 h p.i. fluorescence-guided prostatectomy using in vivo and ex vivo fluorescence detection was performed. This research was originally published in JNM, Baranski et al., PSMA-11-Derived Dual-Labeled PSMA Inhibitors for Preoperative PET Imaging and Precise Fluorescence-Guided Surgery of Prostate Cancer, J Nucl Med, 2017, © SNMMI .

Figure 7

Chemical structures of different PSMA-targeted photosensitizer conjugates and example photodynamic therapy (PDT) efficacy of LC-Pyro in vivo. (A) Chemical structures of Ppa-CTT-54 [1] and LC-Pyro [2]. (B) PDT efficacy of LC-Pyro in PSMA⁺ PC3-PIP s.c. tumor-bearing mice. Tumor growth curves (mean ±SD, n = 4 for each group, ***P ≤ 0.001, n.s. = not significant). (C) Representative images of tumor-burdened mice in saline only, laser only, LC-Pyro only, and LC-Pyro + Laser groups at 0, 6, and 22 days post-PDT treatment. (D) Chemical structures of PSMA-1-IR700 [3] and YC9 [4]. Reprinted and adapted with permission from Harmatys et al., Tuning pharmacokinetics to improve tumor accumulation of a prostate-specific membrane antigen-targeted phototheranostic agent, Copyright 2018, American Chemical Society .