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-PEG(12)-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 (IC(50) values: 1.21, 2.53, and 10nM, respectively) and irreversibility; but only biotin-PEG(12)-CTT54 demonstrated specifically labeling PSMA-positive prostate cancer cells in a two-step pretargeting procedure. Additionally, the pre-formulated complex between biotin-PEG(12)-CTT54 and Cy5-streptavidin displayed the improved inhibitory potency (IC(50)=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.
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
authors.forename: Tiancheng
authors.initials: T
authors.lastname: Liu
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Nedrow-Byers
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hopkins
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Wu
authors.forename: Jeonghoon
authors.initials: J
authors.lastname: Lee
authors.forename: Peter T A
authors.initials: PT
authors.lastname: Reilly
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism*; D001360:Avidin / Q000737:chemistry; D001710:Biotin / Q000737:chemistry; D019921:Biotinylation; D002232:Carbocyanines; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D005453:Fluorescence; D005456:Fluorescent Dyes; D043425:Glutamate Carboxypeptidase II / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D008856:Microscopy, Fluorescence; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019809:Streptavidin / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D002232:Carbocyanines; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D018796:Immunoconjugates; D009943:Organophosphorus Compounds; C085321:cyanine dye 5; D001360:Avidin; D011092:Polyethylene Glycols; D001710:Biotin; D019809:Streptavidin; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II