A phosphoramidate‐based prostate‐specific membrane antigen‐targeted SPECT agent

Nedrow, Jessie R.; Jabbes, Mohamed; Jewett, Cayla; Ganguly, Tanushree; He, Haiyang; Liu, Tiancheng; Benny, Paul D.; Bryan, Jeffrey N.; Berkman, Clifford E.

doi:10.1002/pros.21493

Cited by 37 publications

(41 citation statements)

References 32 publications

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“…One of the rational and effective strategies is to deliver drugs to tumor cells using targeting ligandmodified nanocarriers. 6,15,[49][50][51][52][53][54] The present study further suggested the benefit of using ligand-modified pH-sensitive micelles for their enhanced targeting ability and receptormediated cellular uptake. 38,39 The results of cellular uptake ( Fig.…”

Section: Discussionmentioning

confidence: 95%

PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking

Gao

et al. 2015

Nanoscale

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The cytotoxicity of chemotherapeutic agents to healthy organs and drug resistance of tumor cells are believed to be the main obstacles to the successful cancer chemotherapy in the clinic. To ensure that anticancer drugs could be delivered to the tumor region, are quickly released from carriers in tumor cells and rapidly escape from endo/lysosomes, YPSMA-1-modified pH-sensitive polymeric micelles, which would be advantageous in recognizing the prostate specific membrane antigen (PSMA), were designed and fabricated for targeted delivery of paclitaxel to tumors based on the pH-sensitive diblock copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and YPSMA-1-PEOz-PLA for treating prostate cancer. HOOC-PEOz-PLA with a critical micelle concentration of 5.0 mg L(-1) was synthesized and characterized by (1)H NMR and gel permeation chromatography. The prepared YPSMA-1-modified micelles, about 30 nm in diameter, exhibited a rapid release behavior at endo/lysosome pH and a favorable ability of fast endo/lysosome escape as observed by confocal microscopy. More importantly, we evidenced for the first time that both endosome and lysosome escape existed for pH-sensitive micelles via real time tracing using confocal microscopy, and the real time endo/lysosome escape process was also presented. The YPSMA-1-modified micelles were very effective in enhancing the cytotoxicity of paclitaxel by increasing the cellular uptake in PSMA-positive 22Rv1 cells, which was verified the correlation with PSMA expression in tumor cells by flow cytometric analysis and confocal microscopy. Moreover, the active targeting and pH-sensitivity endowed YPSMA-1-modified micelles with a higher antitumor efficacy and negligible systemic toxicity in 22Rv1 xenograft-bearing nude mice compared with unmodified micelles and Taxol®. These results suggested that the application of combining YPSMA-1 modification with pH-sensitivity to polymeric micelles may be one approach in the efficient delivery of anticancer drugs for treating PSMA-positive prostate cancers.

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Section: Discussionmentioning

confidence: 95%

PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking

Gao

et al. 2015

Nanoscale

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“…Several phosphoramidate inhibitors for optical [109, 113] and SPECT [114, 115] imaging have been reported. 18 F-Fluorobenzoyl phosphoramidate 1 (Fig.…”

Section: New Psma-based Pet Tmaging Agentsmentioning

confidence: 99%

PET Imaging in Prostate Cancer: Focus on Prostate-Specific Membrane Antigen

Mease

Foss²,

Pomper³

2013

CTMC

163

117

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Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Positron emission tomography/computed tomography (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions and, ultimately, for predicting the aggressiveness of disease. Prostate-specific membrane antigen (PSMA) is a well-characterized imaging biomarker of PCa. Because PSMA levels are directly related to androgen independence, metastasis and progression, PSMA could prove an important target for the development of new radiopharmaceuticals for PET. Preclinical data for new PSMA-based radiotracers are discussed and include new 89Zr- and 64Cu-labeled anti-PSMA antibodies and antibody fragments, 64Cu-labeled aptamers, and 11C-, 18F-, 68Ga-, 64Cu-, and 86Y-labeled low molecular weight inhibitors of PSMA. Several of these agents, namely 68Ga-HBED-CC conjugate 15, 18F-DCFBC 8, and BAY1075553 are particularly promising, each having detected sites of PCa in initial clinical studies. These early clinical results suggest that PET/CT using PSMA-targeted agents, especially with compounds of low molecular weight, will make valuable contributions to the management of PCa.

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“…Owing to its unique and ubiquitous expression in prostate cancers (PCa) with limited (100–1000 fold lower) expression in other organs, prostate-specific membrane antigen (PSMA) is an ideal biomarker [1] and has attracted significant attention as a target for imaging [2–7] and treatment of PCa [8–10]. …”

Section: Introductionmentioning

confidence: 99%

“…When conjugated with a fluorescent dye, 1 was found to accumulate in PSMA(+) cells presumably through the internalization of the PSMA enzyme-inhibitor complex [19]. This phosphoramidate inhibitor 1 has also been validated for SPECT and PET imaging of with PSMA(+) cells and tumors when labeled with 99m Tc and 18 F respectively [6,7,20]. …”

Section: Introductionmentioning

confidence: 99%

A high-affinity [18F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

Ganguly

Dannoon²,

Hopkins

et al. 2015

Nuclear Medicine and Biology

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Introduction In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. Methods p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [18F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(−) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. Results The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [18F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(−) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h. Conclusions We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [18F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. Advances in Knowledge The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [18F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.

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A phosphoramidate‐based prostate‐specific membrane antigen‐targeted SPECT agent

Abstract: While DTPA may not represent the ideal chelate structure for 99mTc(CO)3, the data provides proof-of-concept support for the development of a next-generation phosphoramidate-based PSMA inhibitor-conjugates for use as SPECT imaging agents.

Cited by 37 publications

References 32 publications

PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking

PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking

PET Imaging in Prostate Cancer: Focus on Prostate-Specific Membrane Antigen

A high-affinity [18F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

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