title: Preclinical evaluation of DO3A-Act-AQ: a polyazamacrocyclic monomeric anthraquinone derivative as a theranostic agent.
abstract: An anthraquinone conjugated macrocyclic chelating agent, 2,2',2″-(10-(2-(9,10-dioxo-9,10-dihydroanthracen-1-ylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid or DO3A-Act-AQ, was synthesized by reacting trisubstituted cyclen (DO3A) with 2-chloro-N-(9,10-dioxo-9,10-dihydro-anthracen-1-yl)-acetamide and radiolabeled with (68)GaCl3 in 84% efficiency and a specific activity of 4.62 MBq/nmol. The IC50 value for BMG-1 cells was 0.1 mM, while the same concentration of DO3A-Act-AQ rendered no significant toxicity in HEK cells. The exposure of BMG-1 cells with 0.1 mM DO3A-Act-AQ displayed a time-dependent increase in apoptosis (40.7% at 4 h and 53% at 24 h), and the effect was 2.8- and 3.6-fold % higher as seen in HEK cells. An increase in S-phase cell population suggested S-phase arrest concomitant with induction of apoptosis in BMG-1 cells reaching to 4.5 times after 24 h with respect to control cells. DNA binding studies on CT-DNA (calf thymus) revealed a quenching pattern in the presence of DO3A-Act-AQ (10-70 μM), and the Stern-Volmer quenching constant was 2.4157 × 10(6) L mol(-1), indicative of strong binding with ds-DNA. A decrease in the positive and negative bands of CT-DNA was seen at 278 nm and 240 nm, respectively, on addition of 0.05 mM of DO3A-Act-AQ in CD studies. (68)Ga-DO3A-Act-AQ was stable in vitro in both PBS and human serum for at least 2 h. The in vivo blood kinetics study performed on normal rabbits indicated fast clearance with t1/2(F) = 40 ± 0.3 min and t1/2(S) = 3 h 30 min ± 0.1 min. Ex vivo biodistribution analysis displayed a favorable tumor-to-muscle ratio of 8.4 after 2 h in athymic nude mice xenografted with BMG-1 cells, suggesting the specificity of (68)Ga-DO3A-Act-AQ toward tumors.
authors.affiliation: Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research & Development Organization , Brig S K Mazumdar Road, Delhi-110054, India.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Adhikari
authors.forename: Anupama
authors.initials: A
authors.lastname: Datta
authors.forename: Manish
authors.initials: M
authors.lastname: Adhikari
authors.forename: Kanchan
authors.initials: K
authors.lastname: Chauhan
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Saw
authors.forename: Abha
authors.initials: A
authors.lastname: Shukla
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D057809:HEK293 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011817:Rabbits; D014018:Tissue Distribution
chemical_list: C000595503:2,2',2''-(10-(2-(9,10-dioxo-9,10-dihydroanthracen-1-ylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; D000880:Anthraquinones; D000970:Antineoplastic Agents; D006573:Heterocyclic Compounds, 1-Ring; C042834:9,10-anthraquinone