Pluronic-based functional polymeric mixed micelles for co-delivery of doxorubicin and paclitaxel to multidrug resistant tumor.

Although doxorubicin (DOX) and paclitaxel (PTX) are widely used in clinic as chemotherapeutics, both drug substances are found to be glycoprotein P (P-gp) substrates which are liable to develop the multidrug resistance (MDR). Additionally, the use of single chemotherapeutic drug has known limitations such as high toxicity profile due to the relatively high doses and limited regimen of clinical application. To this end, Pluronic P105-DOX conjugate was successfully designed and developed which can be further used as a hydrophobic core to entrap another anti-cancer drug PTX with Pluronic F127 to form the dual drug-loaded mixed micelles (PF-DP) in our study, which would offer great advantages over conventional micelles, including easy fabrication, high loading capacity, and co-delivery of hydrophilic DOX and hydrophobic PTX to achieve synergistic effect of these two drug substances. Results showed that PF-DP possessed a good polydispersity and sustained release profile for both DOX and PTX in vitro. Studies on cellular uptake demonstrated both anti-cancer drugs in PF-DP can effectively accumulate in MDR cancer cells. Furthermore, in vitro cytotoxicity, cell apoptosis and cell cycle arrest studies indicated that PF-DP had better antitumor efficacy in MDR cancer cells compared to those of single-drug loaded micelles. It was also found that PF-DP can suppress the growth of tumor cells more efficiently than single drug formulations at the equivalent drug concentrations, suggesting synergistic effect could be achieved. More importantly, a much stronger antitumor efficacy in MCF-7/ADR tumor-bearing mice was observed in PF-DP group than that of combined administration of free DOX and PTX. Collectively, the dual drug-loaded Pluronic-based functional mixed micelles developed in this study might be a potential nano-drug delivery system for MDR cancer chemotherapy.

Chen Y ，Zhang W ，Huang Y ，Gao F ，Sha X ，Fang X ... -  《-》

Targeted doxorubicin nanotherapy strongly suppressing growth of multidrug resistant tumor in mice.

The rational design of nanomedicine to treat multidrug resistant (MDR) tumors in vivo is described in the study. We prepared multifunctionalized Pluronic micelles that are already well-established to be responsive to low pH and redox in order to systemically deliver doxorubicin (DOX) to MDR tumors. Folic acids (FAs) were introduced on the micelle surface as tumor-targeting molecules. In vitro, the DOX-loaded micelles exerted high cytotoxicity in the DOX-resistant cells by bypassing MDR efflux. Cellular uptake studies clearly demonstrated that FA-conjugated DOX micelles (FA/DOX micelles) were efficiently internalized and accumulated in the MDR cells. In vivo studies indicated significant efficacy of FA/DOX micelles for MDR tumors in mice, and that the volume of tumors was 3 times smaller in this group than that of tumors in the free DOX group, and 8 times smaller than the tumors in the saline group. To the best of our knowledge, this methodology has been recognized to have significantly high efficacy, compared to previously reported DOX nanoparticle formulations. This superior anti-tumor efficacy of FA/DOX micelles in MDR tumor-bearing mice can be attributed to FA-targeted and -mediated endocytosis, inhibition of MDR effect, and subsequent DOX release triggered by dual stimuli (low pH and redox) inside the tumor. Given the promise of the multifunctional micelle mediated delivery on inhibition of MDR tumor growth, FA/DOX micelle platform is a much sought after goal for cancer chemotherapy, especially for cancers resistant to anticancer drugs.

Nguyen DH ，Lee JS ，Bae JW ，Choi JH ，Lee Y ，Son JY ，Park KD ... -  《-》

[Preparation, characterization of paclitaxel-loaded Pluronic P105 polymeric micelles and in vitro reversal of multidrug resistant tumor].

Wang YZ ，Fang XL ，Li YJ ，Zhang ZW ，Han LM ，Sha XY ... -  《-》

Mechanism of inhibition of P-glycoprotein mediated efflux by Pluronic P123/F127 block copolymers: relationship between copolymer concentration and inhibitory activity.

The aim of this study was to clarify the relationship between the concentration of Pluronic P123/F127 block copolymers and P-glycoprotein (P-gp) inhibitory potency. Modulation of multidrug resistance (MDR) by Pluronic P123/F127 was evaluated in P-gp over-expressing human breast cancer cell line MCF-7/ADR and its non-P-gp over-expressing counterpart MCF-7 cells. Four different probes (known as P-gp substrates) including rhodamine 123 (R-123), rhodamine 6G (R-6G), doxorubicin (DOX), and paclitaxel (PTX) were applied to investigate the impact of Pluronic P123/F127 copolymers with different concentrations on the intracellular accumulation of these probes. Additionally, the intracellular ATP and mitochondrial transmembrane potential in MCF-7/ADR cells were determined over a wide concentration range of Pluronic P123/F127. Furthermore, the endocytic mechanisms of Pluronic micelles were performed. It was suggested that P-gp substrate hydrophobicity and the concentration of P123/F127 copolymers had little impact on P-gp inhibitory activity of Pluronic P123/F127 itself. Intracellular ATP depletion was the main mechanism of Pluronic P123/F127 for P-gp inhibition. In vitro cytotoxicity study was also conducted in order to compare cytotoxic effect among different PTX formulations. It indicated that the IC50 of PTX-loaded Pluronic P123/F127 mixed micelles was 6.3-fold lower than free PTX and 2.3-fold lower than Taxol, respectively. Therefore, Pluronic P123/F127 polymeric micelles could be considered a promising drug delivery system to overcome MDR in cancer therapy.

Wei Z ，Yuan S ，Hao J ，Fang X ... -  《-》

Multifunctional Pluronic P123/F127 mixed polymeric micelles loaded with paclitaxel for the treatment of multidrug resistant tumors.

The aim of this study was to exploit the possibility of combination of active targeting function of folic acid by folate receptor-mediated endocytosis and overcoming multidrug resistance (MDR) by Pluronic block copolymers to promote drug delivery to MDR tumor following intravenous administration with paclitaxel (PTX) as model drug. Folic acid functionalized Pluronic P123/F127 mixed micelles encapsulating PTX (FPF-PTX) was firstly developed and tested in vitro and in vivo, while PTX-loaded Pluronic P123/F127 mixed micelles (PF-PTX) and Taxol were used as control. FPF-PTX was about 20 nm in diameter with spherical shape and high encapsulation efficiency. Cellular uptake of FPF-PTX was found to be higher than that of PF-PTX due to the folate receptor-mediated endocytosis effect. In vitro cytotoxicity, cell apoptosis and cell cycle arrest studies also revealed that FPF-PTX was more potent than those of PF-PTX and Taxol. In vivo pharmacokinetic study in rats showed that the polymeric micelles significantly enhanced the bioavailability of PTX (∼3 fold) than Taxol. Moreover, in BALB/c mice bearing KBv MDR tumor xenografts, stronger antitumor efficacy was shown in FPF-PTX group, with good correlation between in vitro and in vivo. In conclusion, folate-conjugated Pluronic micelles could be a potential vehicle for delivering hydrophobic chemotherapeutic drugs to MDR tumors.

Zhang W ，Shi Y ，Chen Y ，Ye J ，Sha X ，Fang X ... -  《-》