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 ... -  《-》

Systematic evaluation of multifunctional paclitaxel-loaded polymeric mixed micelles as a potential anticancer remedy to overcome multidrug resistance.

Multidrug resistance (MDR) of tumor cells is becoming the main reason for the failure of chemotherapy and P-glycoprotein (P-gp) mediated drug efflux has demonstrated to be the key factor for MDR. To address this issue, a novel pH-responsive mixed micelles drug delivery system composed of dextran-g-poly(lactide-co-glycolide)-g-histidine (HDP) and folate acid-D-α-tocopheryl polyethylene glycol 2000 (FA-TPGS2K) copolymers has been designed for the delivery of antitumor agent, paclitaxel (PTX) via FA-receptor mediated cell endocytosis, into PTX-resistant breast cancer MCF-7 cells (MCF-7/PTX). PTX-loaded FA-TPGS2K/HDP mixed micelles were characterized to have a small size distribution, high loading content and excellent pH-responsive drug release profiles. Compared with HDP micelles, FA-TPGS2K/HDP mixed micelles showed a higher cytotoxicity against MCF-7 and MCF-7/PTX cells due to the synergistic effect of FA-receptor mediated cell endocytosis, pH-responsive drug release and TPGS mediated P-gp inhibition. P-gp expression level, ATP content and mitochondrial membrane potential change have been measured, the results indicated blank FA-TPGS2K/HDP mixed micelles could inhibit the P-gp activity by reducing the mitochondrial membrane potential and depleting ATP content but not down-regulating the P-gp expression. In vivo antitumor activities demonstrated FA-TPGS2K/HDP mixed micelles could reach higher antitumor activity compared with HDP micelles for MCF-7/PTX tumor cells. Histological assay also indicated that FA-TPGS2K/HDP mixed micelles showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. All these evidences demonstrated this pH-sensitive FA-TPGS2K/HDP micelle-based drug delivery system is a promising approach for overcoming MDR. In this work, a novel FA-TPGS2K copolymer has been synthesized and used it to construct mixed micelles with HDP copolymer to overcome MDR effect. Furthermore, a series in vitro and in vivo evaluations have been made, which supported enough evidences for the efficient delivery of antitumor drug to MDR cells.

Zhang J ，Zhao X ，Chen Q ，Yin X ，Xin X ，Li K ，Qiao M ，Hu H ，Chen D ，Zhao X ... -  《-》

Comparison of hyaluronic acid-based micelles and polyethylene glycol-based micelles on reversal of multidrug resistance and enhanced anticancer efficacy in vitro and in vivo.

Wang J ，Li Y ，Wang L ，Wang X ，Tu P ... -  《-》

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 ... -  《-》

Micelles of d-α-Tocopheryl Polyethylene Glycol 2000 Succinate (TPGS 2K) for Doxorubicin Delivery with Reversal of Multidrug Resistance.

Hao T ，Chen D ，Liu K ，Qi Y ，Tian Y ，Sun P ，Liu Y ，Li Z ... -  《-》