Mixed Micelles for Targeted and Efficient Doxorubicin Delivery to Multidrug-Resistant Breast Cancer Cells.

For efficient treatment of multidrug-resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)-grafted hyaluronic acid (HA) copolymers (PPG-g-HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG-g-HA/L61 micelles. Optimized PPG-g-HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF-7 MDR cells via HA-CD44-specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG-g-HA/L61 micelles with 3% pluronic L61 have toxicity in MCF-7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG-g-HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase-sensitive manner without any toxicity to normal cells.

Jung H ，Mok H 《-》

pH-sensitive micelles for the intracellular co-delivery of curcumin and Pluronic L61 unimers for synergistic reversal effect of multidrug resistance.

Hong W ，Shi H ，Qiao M ，Zhang Z ，Yang W ，Dong L ，Xie F ，Zhao C ，Kang L ... -  《Scientific Reports》

Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin.

P-glycoprotein (P-gp) mediated drug efflux has been recognized as a key factor contributing to the multidrug resistance (MDR) in tumor cells. To address this issue, a new pH-sensitive mixed copolymer micelles system composed of hyaluronic acid-g-poly(l-histidine) (HA-PHis) and d-α-tocopheryl polyethylene glycol 2000 (TPGS2k) copolymers was developed to co-deliver doxorubicin (DOX) and TPGS2k into drug-resistant breast cancer MCF-7 cells (MCF-7/ADR). The DOX-loaded HA-PHis/TPGS2k mixed micelles (HPHM/TPGS2k) were characterized to have a unimodal size distribution, high DOX loading content and a pH dependent drug release profile due to the protonation of poly(l-histidine). As compared to HA-PHis micelles (HPHM), the HPHM/TPGS2k showed higher and comparable cytotoxicity against MCF-7/ADR cells and MCF-7 cells, respectively. The enhanced MDR reversal effect was attributed to the higher amount of cellular uptake of HPHM/TPGS2k in MCF-7/ADR cells than HPHM, arising from the inhibition of P-gp mediated drug efflux by TPGS2k. The measurements of P-gp expression level and mitochondrial membrane potential indicate that the blank HPHM/TPGS2k inhibited P-gp activity by reducing mitochondrial membrane potential and depletion of ATP but without inhibition of P-gp expression. In vivo study of micelles in tumor-bearing mice indicate that HPHM/TPGS2k could reach the tumor site more effectively than HPHM. The pH-sensitive mixed micelles system has been demonstrated to be a promising approach for overcoming the MDR.

Qiu L ，Qiao M ，Chen Q ，Tian C ，Long M ，Wang M ，Li Z ，Hu W ，Li G ，Cheng L ，Cheng L ，Hu H ，Zhao X ，Chen D ... -  《-》

Reversing multidrug resistance by intracellular delivery of Pluronic® P85 unimers.

Pluronics have been demonstrated as excellent multidrug resistance (MDR) reversal agent in the form of unimers rather than micelles. However, the effective intracellular delivery of Pluronic(®) unimers to MDR cancer cells still remains a big challenge. To address this issue, a mixed micellar system based mainly on the pH-sensitive copolymer of poly (L-histidine)-poly (D,L-lactide)-polyethyleneglycol-poly (D,L-lactide)-poly (L-histidine) (PHis-PLA-PEG-PLA-PHis) and Pluronic(®) F127, some of which was conjugated with folate, was constructed to intracellularly deliver the unimers of Pluronic(®) P85 to MDR cells. The folate-mediated endosomal pH-sensitive mixed micelles (pHendoSM-P85/f) were prepared by a thin-film hydration method, by which Pluronic(®) P85 unimers and doxorubicin (DOX) were incoporated into the mixed micelles. The incorporation of Pluronic(®) P85 unimers was investigated by the surface tension test. The results indicated that the Pluronic(®) P85 unimers probably first inserted into the binary mixed micelles and then formed a triple-component mixed micelles with Pluronic(®) F127 and PHis-PLA-PEG-PLA-PHis as the loading content increased. Further analyzed with flow cytometry, confocal laser scanning microscopy (CLSM) and MTT assay, the micelles with inserted Pluronic(®) P85 unimers demonstrated much more cellular uptake and higher cytotoxicity against MDR cells than the triple-component mixed micelles and plain Pluronic(®) micelles. The enhanced MDR reversal effect was attributed to the successful intracellular delivery of Pluronic(®) P85 unimers to the MDR cells, which was confirmed by the subcellular colocalization of Pluronic(®) P85 unimers with mitochondria, the decreased ATP energy and mitochondrial membrane potential (MP) in the MCF-7/ADR cells. The pHendoSM-P85/f/DOX also demonstrated more dramatic antitumor efficiency and remarkable reduction of ATP energy in the MDR cells in tumors than the control formulations. The intracellular delivery of Pluronic(®) P85 unimers to the MDR cells based on the targeted and endosomal pH triggerd release mixed micelles has been demonstrated as a promising approach to reverse MDR.

Hong W ，Chen D ，Zhang X ，Zeng J ，Hu H ，Zhao X ，Qiao M ... -  《-》

Multifunctionalized Micelles Facilitate Intracellular Doxorubicin Delivery for Reversing Multidrug Resistance of Breast Cancer.

Cao A ，Ma P ，Yang T ，Lan Y ，Yu S ，Liu L ，Sun Y ，Liu Y ... -  《-》