Multidrug resistance （MDR） of breast cancer is a major cause of failure in chemotherapy. In the present study, a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed （DSPE-PEG2000-PMT） conjugate was synthesized from DSPE-PEG2000-NH2 and pemetrexed, and targeted sunitinib plus vinorelbine liposomes were developed by modifying DSPE-PEG20o0-PMT onto the surface of liposomes to overcome the MDR of breast cancer. The synthesized DSPE-PEG2000-PMT was confirmed to be consistent with the target product by matrix-assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF-MS）. The concentrations of sunitinib and vinorelbine were measured simultaneously by high performance liquid chromatography （HPLC）. The analysis was performed on an ODS column at 30℃ at a wavelength of 215 nm with the mobile phase consisting of acetonitrile, 0.05 M KH2PO4 （pH 3.5） and triethylamine （35：65：0.3, v/v/v）. The limits of detection for sunitinib and vinorelbine were 25 ng/mL and 5 ng/mL, respectively, and the limits of quantification for both drugs were 0.25μg/mL. Two drugs were linearly correlated in the range of 0.5-25.0 μg/mL. For varying types of liposomes, the encapsulation efficiencies were 〉90%; the particle sizes were approximately 90 nm, and zeta potentials were slightly negative. The inhibitory effects were evaluated in the resistant breast cancer MCF-7/Adr cells. The results revealed that targeted sunitinib plus vinorelbine liposomes exhibited the strongest inhibitory effect to the resistant MCF-7/Adr cells among the varying formulations. Targeted coumarin liposomes were used as a fluorescent probe to evaluate the targeting effect to resistant breast cancer MCF-7/Adr cells. The results demonstrated that the targeted coumarin liposomes displayed the highest cellular uptake compared to non-targeted formulations. In conclusion, the targeted sunitinib plus vinorelbine liposomes represented a novel type of nano-formulations, which could accumulate in the resistant breast
Most of antieancer agents can not be used for treatment of brain glioma due to the existence of the blood brain barrier （BBB）. The over-expression of glucose transporters （GLUTs） on the BBB and brain glioma cells enables the possibility that the GLUTs ligand modified drug carrier transports across the BBB, and targets to the brain glioma cells. The objectives of the present study were to synthesize a new glucose conjugate material, TPGS1000-Glu, develop a kind of TPGSI00o-Glu modified epirubicin liposomes, and evaluate their efficacy. The studies were performed on the BBB co-culture model and brain glioma cells in vitro. TPGS 1000-Glu was synthesized by conjugating TPGSlo00_COOH with 4-aminophenyl-[3-D-glucopyranoside （Glu）, and confirmed by MALDI-TOF-MS spectrum. TPGS^0oo-GIu modified epirubicin liposomes were prepared with a high drug encapsulation efficiency （〉97%）, a nanosize （approximately 90 nm）, and a minimal drug leakage in fetal bovine serum （FBS）-containing buffer system. The BBB co-culture model was established, and after applying TPGSl0oo-Glu modified epirubicin liposomes to the model, transport of liposomal drug across the BBB was evidenced. Besides, TPGS1000-Glu modified epirubicin liposomes showed the strongest cellular drug uptake and anti-glioma efficacy after transport across the BBB in vitro. The synthesized TPGS1000-Glu material could offer a new targeting ligand for the BBB, while the developed TPGS1000-Glu modified epirubicin liposomes might provide a potential anticancer formulation for treatment of brain glioma.
Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor（ER）, progesterone receptor（PR） and human epidermal growth factor receptor-2（HER2）. A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicin and rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.
