Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate

Tiancheng Liu; Jessie R Nedrow-Byers; Mark R Hopkins; Lisa Y Wu; Jeonghoon Lee; Peter T.A Reilly; Clifford E Berkman

doi:10.1016/j.bmcl.2012.04.110

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Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate

Journal article

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Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate

Tiancheng Liu, Jessie R Nedrow-Byers, Mark R Hopkins, Lisa Y Wu, Jeonghoon Lee, Peter T.A Reilly and Clifford E Berkman

Bioorganic & medicinal chemistry letters, Vol.22(12), pp.3931-3934

06/15/2012

DOI: https://doi.org/10.1016/j.bmcl.2012.04.110

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https://hdl.handle.net/2376/116337

PMCID: PMC3526141

PMID: 22607680

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https://doi.org/10.1016/j.bmcl.2012.04.110View

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Abstract

Streptavidin–biotin system

Prostate cancer

Biotinylated PSMA inhibitor

Tumor-targeting imaging

A series of spacer-varied biotinylated PSMA inhibitors were synthesized and evaluated, which exhibited spacer length-dependent effects on inhibitory potency, mode of inhibition. Moreover, only one of them can be used to form a complex with Cy5-streptavidin for fluorescence imaging of prostate cancer cells. Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, its high expression is associated with prostate cancer progression, and has been becoming an active target for imaging or therapeutic applications for prostate cancer. On the other hand, streptavidin–biotin system has been successfully employed in pretargeting therapy towards multiple cancers. Herein, we describe the synthesis of bifunctional ligands (biotin-CTT54, biotin-PEG4-CTT54, and biotin-PEG12-CTT54) possessing two functional motifs separated by a length-varied polyethylene glycol (PEG) spacer: one (CTT54) binds tumor-marker PSMA and the other (biotin) binds streptavidin or avidin. All three compounds exhibited high potencies (IC50 values: 1.21, 2.53, and 10nM, respectively) and irreversibility; but only biotin-PEG12-CTT54 demonstrated specifically labeling PSMA-positive prostate cancer cells in a two-step pretargeting procedure. Additionally, the pre-formulated complex between biotin-PEG12-CTT54 and Cy5-streptavidin displayed the improved inhibitory potency (IC50=1.86nM) and irreversibility against PSMA and rapid uptake of streptavidin conjugate into PSMA-positive prostate cancer cells through PSMA-associated internalization. Together, all these results supported a proof-concept that combination of streptavidin and PSMA’s biotinylated inhibitor may lead to development of a novel strategy of tumor-targeting imaging or drug delivery towards prostate cancer.

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Title: Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate
Creators: Tiancheng Liu - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Jessie R Nedrow-Byers - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Mark R Hopkins - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Lisa Y Wu - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Jeonghoon Lee - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Peter T.A Reilly - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Clifford E Berkman - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Publication Details: Bioorganic & medicinal chemistry letters, Vol.22(12), pp.3931-3934
Academic Unit: Chemistry, Department of
Publisher: Elsevier Ltd
Identifiers: 99900547690301842
Language: English
Resource Type: Journal article