Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Hensbergen, Albertus W.; Willigen, Danny M. van; Beurden, Florian van; Leeuwen, Pim J. van; Buckle, Tessa; Schottelius, Margret; Maurer, Tobias; Wester, Hans‐Jürgen; Leeuwen, F.W.B. van

doi:10.1021/acs.bioconjchem.9b00758

Cited by 42 publications

(34 citation statements)

References 127 publications

(263 reference statements)

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“…Truncation of the homotypical P0-protein into peptides yielded Cy5-P0 101–125 as lead compound. In vitro and in vivo studies indicate that this compound is able to provide nerve-specific staining with nanomolar affinity, which is in the same range as reported affinities for other fluorescently labelled targeted tracers [ 36 , 47 , 48 ]. Specificity of Cy5-P0 101–125 for P0 was shown both in vitro (Fig.…”

Section: Discussionsupporting

confidence: 65%

Intraoperative visualization of nerves using a myelin protein-zero specific fluorescent tracer

et al. 2021

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Background Surgically induced nerve damage is a common but debilitating side effect in oncological surgery. With the aim to use fluorescence guidance to enable nerve-sparing interventions in future surgery, a fluorescent tracer was developed that specifically targets myelin protein zero (P0). Results Truncated homotypic P0 protein-based peptide sequences were C-terminally functionalized with the far-red cyanine dye Cy5. The lead compound Cy5-P0101–125 was selected after initial solubility, (photo)physical and in vitro evaluation (including P0-blocking experiments). Cy5-P0101–125 (KD = 105 ± 17 nM) allowed in vitro and ex vivo P0-related staining. Furthermore, Cy5-P0101–125 enabled in vivo fluorescence imaging of the Sciatic nerve in mice after local intravenous (i.v.) administration and showed compatibility with a clinical fluorescence laparoscope during evaluation in a porcine model undergoing robot-assisted surgery. Biodistribution data revealed that i.v. administered [111In]In-DTPA-P0101–125 does not enter the central nervous system (CNS). Conclusion P0101–125 has proven to be a potent nerve-specific agent that is able to target P0/myelin under in vitro, ex vivo, and in vivo conditions without posing a threat for CNS-related toxicity.

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Section: Discussionsupporting

confidence: 65%

Intraoperative visualization of nerves using a myelin protein-zero specific fluorescent tracer

et al. 2021

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“…thus only a small urine layer must be considered (24,31)). Nonetheless, acknowledgement of this effect by radiochemists (32,33) and the reduced renal clearance of for example [ 18 F]F-PSMA tracers (34,35) may in the future help to overcome these issues. In addition, the in uence of renal clearance might also be overcome by using b-emitting isotopes that have a longer half-life, allowing the tumor resection to take place after all renal clearance of non-bound tracer is realized, e.g.…”

Section: Discussionmentioning

confidence: 99%

A DROP-IN beta probe for robot-assisted 68Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens

Collamati

OOsterom

Simoni

et al. 2020

Preprint

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Background: Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET-isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET-tracers during robot-assisted tumor-receptor-targeted. In this study, we’ve engineered and validated the performance of a novel DROP-IN beta-particle (DROP-INb) detector.Methods: Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of ~70 MBq 68Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-INb probe prototype, which merged a scintillating detector with a housing optimized for a 12 mm trocar and prograsp instruments. Results: After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-INb probe prototype was tested in a robotic setting. In the ex vivo setting, the probe – positioned by the robot- was able to identify 68Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located <1 mm below the specimen surface. 68Ga-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-INb probe (S/B>3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta tracing. Conclusions: This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-INb detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes.

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“…PSMA, also named glutamate carboxypeptidase II, is overexpressed in over 90% prostate cancer patients. [46] A class of urea-based PSMA inhibitors, including 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) and lysine-urea-glutamate (KuE), were utilized to conjugate with multifarious cyanine scaffolds and linker structures for intraoperative imaging of prostate cancer. [47] OTL78 (35) and YC-27 (36) are two representative conjugates based on DUPA and KuE, respectively.…”

Section: Probes For Enzymesmentioning

confidence: 99%

Cyanine Conjugate‐Based Biomedical Imaging Probes

Zhou

Yue

et al. 2020

Adv Healthcare Materials

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Cyanine is a class of fluorescent dye with meritorious fluorescence properties and has motivated numerous researchers to explore its imaging capabilities by miscellaneous structural modification and functionalization strategies. The covalent conjugation with other functional molecules represents a distinctive design strategy and has shown immense potential in both basic and clinical research. This review article summarizes recent achievements in cyanine conjugate-based probes for biomedical imaging. Particular attention is paid to the conjugation with targeting warheads and other contrast agents for targeted fluorescence imaging and multimodal imaging, respectively. Additionally, their clinical potential in cancer diagnostics is highlighted and some concurrent impediments for clinical translation are discussed.

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Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Cited by 42 publications

References 127 publications

Intraoperative visualization of nerves using a myelin protein-zero specific fluorescent tracer

Intraoperative visualization of nerves using a myelin protein-zero specific fluorescent tracer

A DROP-IN beta probe for robot-assisted 68Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens

Cyanine Conjugate‐Based Biomedical Imaging Probes

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