Development of multidrug resistance against chemotherapeutic drugs is one of the major obstacles to successful cancer therapy in the clinic. Thus far, amphiphilic polymeric micelles and chemosensitizers have been used to overcome multidrug resistance in cancer. The goals of this study were to prepare poly(ethylene glycol)-bock-poly(lactide) (PEG(2k)-PLA(5k)) micelles for co-delivery of the chemotherapeutic drug doxorubicin (DOX) with a chemosensitizer curcumin (CUR), investigate the potential of the dual drug-loaded micelles ((DOX+CUR)-Micelles) to reverse multidrug resistance, and explore the underlying mechanisms. (DOX + CUR)-Micelles were prepared using an emulsion solvent evaporation method. The cellular uptake, drug efflux, down-regulation of P-glycoprotein expression and inhibition of ATP activity of (DOX+ CUR)-Micelles were studied in drug-resistant MCF-7/ADR cells. In vitro analyses demonstrated that (DOX + CUR)-Micelles were superior to free DOX, free drug combination (DOX + CUR), and DOX-loaded micelles in inhibiting proliferation of MCF-7/ADR cells. This effect of (DOX + CUR)-Micelles was partially attributable to their highest cellular uptake, lowest efflux rate of DOX, and strongest effects on down-regulation of P-glycoprotein and inhibition of ATP activity. Additionally, (DOX+CUR)-Micelles showed increased tumor accumulation and strong inhibitory effect on tumor growth in the xenograft model of drug-resistant MCF-7/ADR cells compared to that of other drug formulations. These results indicate that (DOX + CUR)-Micelles display potential for application in the therapy of drug-resistant breast carcinoma.
The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug–loaded nanoparticles, or non-biotin–decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo, among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer.
By using the synthetic method, the solubilities of benzoic acid in binary methylbenzene + benzyl alcohol solvent mixtures at (301.05 to 355.65) K and in binary methylbenzene + benzaldehyde solvent mixtures at (301.05 to 354.45) K were determined at atmospheric pressure. The studied mass fractions of benzyl alcohol and benzaldehyde in the corresponding binary solvent mixtures range from 0.0 to 1.0. It was found that the measured solubilities increase with the increase of temperature at constant solvent composition. For the ternary system benzoic acid + methylbenzene + benzyl alcohol, the results show that the binary methylbenzene + benzyl alcohol solvent mixture with the mass fraction of benzyl alcohol at 0.80 has the best dissolving capacity for benzoic acid at constant temperature. However, for the ternary system benzoic acid + methylbenzene + benzaldehyde, the results show that the binary methylbenzene + benzaldehyde solvent mixture with the mass fraction of benzaldehyde of 0.20 has the best dissolving capacity for benzoic acid at constant temperature. The experimental data were correlated by both the nonrandom two-liquid (NRTL) and the Apelblat equations, and the correlated solubilities agree satisfactorily with the experimental observations. By coupling the Apelblat equation with the Clark and Glew equation, the thermodynamic functions for the two studied solid−liquid equilibrium systems, including dissolution enthalpy, entropy, Gibbs energy, and isobaric heat capacity, were calculated and discussed.
The purities of p-ClTPP were checked by using a Shimadzu-15C high-performance liquid chromatography (HPLC). Inertsil ODS-3 (250 mm × 4.6 mm, 5 µm) chromatographic column was used. The mobile phase was constituted of 40 mass % methanol + 55 mass % acetonitrile + 5 mass % tetrahydrofurane, and the flow rate was 1 mL/min.Each analysis last about 10 min. 424 nm was chosen as the measurement wavelength. p-ClTPP used for standard samples was purified by column chromatography at least twice, and the corresponding HPLC chromatogram was shown in Figure S1. The peak at 4.32min represented p-ClTPP, and the chromatographic purity could be determined to be 1709675/(1709675+16170)=0.991. p-ClTPP used for solid-liquid equilibria were synthesized by the traditional Adler method 1 , and were used without further purification. The corresponding HPLC chromatogram was shown in Figure S2. The peak at 4.32min represented p-ClTPP, and the chromatographic purity could be determined to be 219917/(219917+5764+3152)=0.961.
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