TY - JOUR
T1 - Synthesis, formulation and in vitro evaluation of a novel microtubule destabilizer, SMART-100
AU - Li, Feng
AU - Lu, Yan
AU - Li, Wei
AU - Miller, Duane D.
AU - Mahato, Ram I.
N1 - Funding Information:
This work is partially supported by the teaching assistantship from the University of Tennessee School of Pharmacy to Feng Li, and Van Vleet Endowed Chair to Duane D. Miller.
PY - 2010/4
Y1 - 2010/4
N2 - 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 1.1×105 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.
AB - 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 1.1×105 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.
KW - Cancer
KW - MDR
KW - Micelles
KW - Microtubule destabilizer
KW - Polymer
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U2 - 10.1016/j.jconrel.2009.12.028
DO - 10.1016/j.jconrel.2009.12.028
M3 - Article
C2 - 20060430
AN - SCOPUS:77950516980
VL - 143
SP - 151
EP - 158
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 1
ER -