title: Synthesis, formulation and in vitro evaluation of a novel microtubule destabilizer, SMART-100.
abstract: A novel microtubule destabilizer, substituted methoxybenzoyl-ary-thiazole (SMART)-100, was synthesized, which showed good anticancer activity in HepG2 cells. SMART-100 was able to circumvent multidrug resistance (MDR) and effectively inhibited the growth of cell lines that overexpress P-glycoprotein (P-gp). SMART-100 inhibited P-gp activity, which may be responsible for its ability to overcome MDR. Since SMART-100 is poorly soluble in water, it was formulated in polyethylene-b-poly(D,L-lactide) (PEG-PLA) micelles. The solubility of SMART-100 was increased by more than 1.1x10(5) folds. SMART-100 loaded PEG-PLA micelles could effectively inhibit HepG2 cell growth and arrest cell cycle progression at G2/M phase, followed by appearance of a sub-G1 phase, which is indicative of cell apoptosis. Increased Caspase-3 activity was also observed when HepG2 cells were treated with SMART-100. The anticancer activity of SMART-100 loaded PEG-PLA micelles was also evaluated on luciferase expressing C4-2-Luc cell lines by IVIS imaging. Our results suggest that SMART-100 has the potential to treat resistant cancers.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007773:Lactates / Q000737:chemistry*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C550330:(2-phenylthiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D007773:Lactates; D008823:Micelles; D013844:Thiazoles; D050257:Tubulin Modulators; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D008156:Luciferases; C505407:CASP3 protein, human; D053148:Caspase 3