PSMA-targeted SPECT agents: Mode of binding effect on in vitro performance
| Autor: | Clifford E. Berkman, Paul D. Benny, Jessie R. Nedrow-Byers, Melody D. Fulton, Adam L Moore, Tanushree Ganguly, Mark R. Hopkins |
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| Rok vydání: | 2012 |
| Předmět: |
Glutamate Carboxypeptidase II
Male Pathology medicine.medical_specialty Cell Survival Urology media_common.quotation_subject Plasma protein binding urologic and male genital diseases Article Prostate cancer Drug Delivery Systems Antigen Cell Line Tumor Glutamate carboxypeptidase II medicine Humans Internalization media_common Radioisotopes Tomography Emission-Computed Single-Photon Chemistry Prostatic Neoplasms medicine.disease In vitro Oncology Cell culture Antigens Surface Cancer research Protein Binding Binding effect |
| Zdroj: | The Prostate. 73:355-362 |
| ISSN: | 0270-4137 |
| Popis: | The enzyme-biomarker prostate-specific membrane antigen (PSMA) is an active target for imaging and therapeutic applications for prostate cancer. The internalization of PSMA has been shown to vary with inhibitors' mode of binding: irreversible, slowly reversible, and reversible.In the present study, PSMA-targeted clickable derivatives of an irreversible phosphoramidate inhibitor DBCO-PEG(4) -CTT-54 (IC(50) = 1.0 nM) and a slowly reversible phosphate inhibitor, DBCO-PEG(4) -CTT-54.2 (IC(50) = 6.6 nM) were clicked to (99m) Tc(CO)(3) -DPA-azide to assemble a PSMA-targeted SPECT agent. The selectivity, percent uptake, and internalization of these PSMA-targeted SPECT agents were evaluated in PSMA-positive and PSMA-negative cells.In vitro studies demonstrated that PSMA-targeted SPECT agents exhibited selective cellular uptake in the PSMA-positive LNCaP cells compared to PSMA-negative PC3 cells. More importantly, it was found that (99m) Tc(CO)(3) -DPA-DBCO-PEG(4) -CTT-54 based on an irreversible PSMA inhibitor core, exhibited greater uptake and internalization than (99m) Tc(CO)(3) -DPA-DBCO-PEG(4) -CTT-54.2 constructed from a slowly reversible PSMA inhibitor core.We have demonstrated that a PSMA-targeted SPECT agent can be assembled efficiently using copper-less click chemistry. In addition, we demonstrated that mode of binding has an effect on internalization and percent uptake of PSMA-targeted SPECT agents; with the irreversible targeting agent demonstrating superior uptake and internalization in PSMA+ cells. The approach demonstrated in this work now supports a modular approach for the assembly of PSMA-targeted imaging and therapeutic agents. |
| Databáze: | OpenAIRE |
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