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

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

Research output: Contribution to journalArticle

Abstract

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-PEG 4-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 10 nM, 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 = 1.86 nM) 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.

Original languageEnglish (US)
Pages (from-to)3931-3934
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number12
DOIs
StatePublished - Jun 15 2012
Externally publishedYes

Fingerprint

Streptavidin
Biotin
Prostatic Neoplasms
Cells
Inhibitory Concentration 50
Imaging techniques
Avidin
Differentiation Antigens
Membrane Glycoproteins
Tumor Biomarkers
Drug delivery
Labeling
human glutamate carboxypeptidase II
Tumors
Neoplasms
Ligands
Therapeutics
Pharmaceutical Preparations

Keywords

  • Biotinylated PSMA inhibitor
  • Prostate cancer
  • Streptavidin-biotin system
  • Tumor-targeting imaging

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate. / Liu, Tiancheng; Nedrow, Jessie; Hopkins, Mark R.; Wu, Lisa Y.; Lee, Jeonghoon; Reilly, Peter T A; Berkman, Clifford E.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 12, 15.06.2012, p. 3931-3934.

Research output: Contribution to journalArticle

Liu, Tiancheng ; Nedrow, Jessie ; Hopkins, Mark R. ; Wu, Lisa Y. ; Lee, Jeonghoon ; Reilly, Peter T A ; Berkman, Clifford E. / Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 12. pp. 3931-3934.
@article{6ee3de708e364d129180788cc0b555bb,
title = "Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate",
abstract = "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-PEG 4-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 10 nM, 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 = 1.86 nM) 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.",
keywords = "Biotinylated PSMA inhibitor, Prostate cancer, Streptavidin-biotin system, Tumor-targeting imaging",
author = "Tiancheng Liu and Jessie Nedrow and Hopkins, {Mark R.} and Wu, {Lisa Y.} and Jeonghoon Lee and Reilly, {Peter T A} and Berkman, {Clifford E.}",
year = "2012",
month = "6",
day = "15",
doi = "10.1016/j.bmcl.2012.04.110",
language = "English (US)",
volume = "22",
pages = "3931--3934",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "12",

}

TY - JOUR

T1 - Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate

AU - Liu, Tiancheng

AU - Nedrow, Jessie

AU - Hopkins, Mark R.

AU - Wu, Lisa Y.

AU - Lee, Jeonghoon

AU - Reilly, Peter T A

AU - Berkman, Clifford E.

PY - 2012/6/15

Y1 - 2012/6/15

N2 - 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-PEG 4-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 10 nM, 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 = 1.86 nM) 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.

AB - 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-PEG 4-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 10 nM, 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 = 1.86 nM) 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.

KW - Biotinylated PSMA inhibitor

KW - Prostate cancer

KW - Streptavidin-biotin system

KW - Tumor-targeting imaging

UR - http://www.scopus.com/inward/record.url?scp=84861575667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861575667&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2012.04.110

DO - 10.1016/j.bmcl.2012.04.110

M3 - Article

VL - 22

SP - 3931

EP - 3934

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 12

ER -