In vitro cytotoxicity of Stealth liposomes co-encapsulating doxorubicin and verapamil on doxorubicin-resistant tumor cells.
Multidrug resistance (MDR) is a major obstacle to successful clinical cancer chemotherapy. A novel doxorubicin anti-resistant Stealth liposomes (DARSLs), prepared by co-encapsulating doxorubicin (DOX) and verapamil (VER) into stealth liposomes, has been developed. The average particle size of DARSLs was 118.1+/-22.3 nm. Encapsulation efficiencies of DOX and VER in DARSLs were greater than 95% and 70%, respectively. The IC(50) of DARSLs as measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay in multidrug resistant rat prostate cancer Mat-LyLu-B2 (MLLB2) cells was 0.079+/-0.017 microM, 13 fold less than that for liposomal DOX with free VER (LDFV 0.96+/-0.46 microM) but only about 2 times less than FDFV. The IC(50) cytotoxicity on MLLB2 cells of the various formulations was as follows: DARSLs approximately LDLV<FDFV<FDLV<LDFV<LD<FD, (LD: liposomal DOX; LV: liposomal VER; FD: free DOX; FV: free VER). Similar cytotoxicities were shown between DARSLs and FDFV in DOX-resistant human uterus sarcoma MES-SA/DX5 cells, reversing DOX-resistance to that shown by FD on DOX-sensitive MES-SA cells. For MLLB2 cells, DARSLs was the most cytotoxic, but its intracellular concentration of DOX, measured as mean cellular fluorescence with flow cytometry was lower (p<0.01) than that observed with the FDFV formulation. In conclusion, DARSLs was an effective DOX formulation which could overcome drug resistance in DOX-resistant tumor cells, but its mechanisms of action may be complex.
Wang
JianCheng
J
Department of Hematology and Oncology, National University Hospital, Singapore.
Goh
BoonCher
B
Lu
WanLiang
W
Zhang
Qiang
Q
Chang
Alex
A
Liu
Xiao Yan
XY
Tan
Theresa M C
TM
Lee
HowSung
H
D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers / Q000008:administration & dosage*; D004339:Drug Compounding / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008081:Liposomes; D014700:Verapamil / Q000008:administration & dosage*
D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin; D014700:Verapamil