title: Design, synthesis, and biological evaluations of tumor-targeting dual-warhead conjugates for a taxoid-camptothecin combination chemotherapy.
abstract: Novel tumor-targeting dual-warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR-, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22-9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid-camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate.
authors.affiliation: Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Vineberg
authors.forename: Edison S
authors.initials: ES
authors.lastname: Zuniga
authors.forename: Anushree
authors.initials: A
authors.lastname: Kamath
authors.forename: Ying-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Seitz
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D001710:Biotin / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D057930:Click Chemistry; D005260:Female; D005978:Glutathione / Q000008:administration & dosage; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy / Q000379:methods*; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D017978:Receptors, Growth Factor; C101719:SB T-1214; D043823:Taxoids; C052136:biotin receptor; D001710:Biotin; D005978:Glutathione; D002166:Camptothecin