A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA)

Banerjee, Sangeeta Ray; Pullambhatla, Mrudula; Shallal, Hassan M.; Lisok, Ala; Mease, Ronnie C.; Pomper, Martin G.

doi:10.18632/oncotarget.415

Cited by 53 publications

(62 citation statements)

References 31 publications

(34 reference statements)

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“…34 Compound 1 (74 mg, 100 μ mol) was reacted with N -boc-1,4-diaminobutane (19 mg, 100 μ mol) and TEA (20 μ L) in CH 2 Cl 2 (2 mL). The reaction was monitored using ESI-MS and evaporated under vacuum upon completion.…”

Section: Methodsmentioning

confidence: 99%

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

et al. 2014

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Differential expression of surface proteins on normal vs malignant cells provides the rationale for the development of receptor-, antigen-, and transporter-based, cancer-selective imaging and therapeutic agents. However, tumors are heterogeneous, and do not always express what can be considered reliable, tumor-selective markers. That suggests development of more flexible targeting platforms that incorporate multiple moieties enabling concurrent targeting to a variety of putative markers. We report the synthesis, biochemical, in vitro, and preliminary in vivo evaluation of a new heterobivalent (HtBv) imaging agent targeting both the prostate-specific membrane antigen (PSMA) and integrin-αvβ3 surface markers, each of which can be overexpressed in certain tumor epithelium and/or neovasculature. The HtBv agent was functionalized with either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or the commercially available IRDye800CW. DOTA-conjugated HtBv probe 9 bound to PSMA or αvβ3 with affinities similar to those of monovalent (Mnv) compounds designed to bind to their targets independently. In situ energy minimization experiments support a model describing the conformations adapted by 9 that enable it to bind both targets. IRDye800-conjugated HtBv probe 10 demonstrated target-specific binding to either PSMA or integrin-αvβ3 overexpressing xenografts. HtBv agents 9 and 10 may enable dual-targeted imaging of malignant cells and tissues in an effort to address heterogeneity that confounds many cancer-targeted imaging agents.

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Section: Methodsmentioning

confidence: 99%

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

et al. 2014

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“…Several investigators have reported on the use of smallmolecule inhibitors of PSMA labeled with 123 I (15-17), 99m Tc (18,19), 18 F (20), 111 In (21), and 68 Ga (22) with potential for imaging PSMA. In the present study, two highaffinity radioiodinated PSMA inhibitors described previously (16,17), 123 I-MIP-1072 and 123 I-MIP-1095, were studied in prostate cancer patients and healthy volunteers under an exploratory investigational new drug (IND) application.…”

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confidence: 99%

First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer

Barrett¹,

et al. 2013

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This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using 123 I-MIP-1072 and 123 I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. Methods: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of 123 I-MIP-1072 and 123 I-MIP-1095 2 wk apart in a crossover trial design. 123 I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2-3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. Results: 123 I-MIP-1072 and 123 I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5-1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4-24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of 123 I-MIP-1072 was approximately 5 times faster. 123 I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of 123 I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for 123 I-MIP-1072 and 123 I-MIP-1095, respectively. Conclusion: 123 I-MIP-1072 and 123 I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1-4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with 131 I therapeutic radiopharmaceuticals.

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“…and Banerjee et al . [43] showed ∼10-fold improvement on the PSMA enzyme inhibitory activity with their multimeric PSMA-binding ligands when comparing to the monomeric ones. Aggarwal et al .…”

Section: Resultsmentioning

confidence: 98%

Evaluation of Phage Display Discovered Peptides as Ligands for Prostate-Specific Membrane Antigen (PSMA)

2013

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The aim of this study was to identify potential ligands of PSMA suitable for further development as novel PSMA-targeted peptides using phage display technology. The human PSMA protein was immobilized as a target followed by incubation with a 15-mer phage display random peptide library. After one round of prescreening and two rounds of screening, high-stringency screening at the third round of panning was performed to identify the highest affinity binders. Phages which had a specific binding activity to PSMA in human prostate cancer cells were isolated and the DNA corresponding to the 15-mers were sequenced to provide three consensus sequences: GDHSPFT, SHFSVGS and EVPRLSLLAVFL as well as other sequences that did not display consensus. Two of the peptide sequences deduced from DNA sequencing of binding phages, SHSFSVGSGDHSPFT and GRFLTGGTGRLLRIS were labeled with 5-carboxyfluorescein and shown to bind and co-internalize with PSMA on human prostate cancer cells by fluorescence microscopy. The high stringency requirements yielded peptides with affinities KD∼1 µM or greater which are suitable starting points for affinity maturation. While these values were less than anticipated, the high stringency did yield peptide sequences that apparently bound to different surfaces on PSMA. These peptide sequences could be the basis for further development of peptides for prostate cancer tumor imaging and therapy.

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A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA)

Cited by 53 publications

References 31 publications

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer

Evaluation of Phage Display Discovered Peptides as Ligands for Prostate-Specific Membrane Antigen (PSMA)

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A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA)

Cited by 53 publications

References 31 publications

Heterobivalent Agents Targeting PSMA and Integrin-αvβ3

Heterobivalent Agents Targeting PSMA and Integrin-αvβ3

First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer

Evaluation of Phage Display Discovered Peptides as Ligands for Prostate-Specific Membrane Antigen (PSMA)

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Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃