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 ... -  《-》

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 ... -  《-》

Folic Acid-Modified Nanoerythrocyte for Codelivery of Paclitaxel and Tariquidar to Overcome Breast Cancer Multidrug Resistance.

Zhong P ，Chen X ，Guo R ，Chen X ，Chen Z ，Wei C ，Li Y ，Wang W ，Zhou Y ，Qin L ... -  《-》

Redox-sensitive mPEG-SS-PTX/TPGS mixed micelles: An efficient drug delivery system for overcoming multidrug resistance.

The main cause of multidrug resistance (MDR) is overexpression of active efflux transporters, such as P-glycoprotein (P-gp). To reverse MDR and improve the chemotherapy effect of paclitaxel (PTX), we propose a new drug delivery system based on mixed micelles constructed with d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) and the mPEG-SS-PTX conjugate with consideration that TPGS is a P-gp inhibitor that can block the cancer cell action of pumping drugs outside of cells and can enhance the anticancer effect. mPEG-SS-PTX is synthesized by conjugating hydrophilic mPEG with a hydrophobic drug, PTX, via a redox-sensitive disulfide bond. The mPEG-SS-PTX conjugate is amphiphilic and can self-assemble in water. Mixed micelles formed by the mPEG-SS-PTX conjugate and TPGS have a low critical micelle concentration (CMC, ∼1.05×10-3mg/mL) and high drug loading content (∼19.6%). The disulfide bond in the mPEG-SS-PTX conjugate can be broken in cancer cells (a reductive environment) and release PTX to kill cancer cells. In vitro cytotoxicity and cell uptake suggest that mixed micelles can effectively improve the accumulation of PTX in multidrug-resistant MCF-7 cells. Therefore, the present as-prepared mixed micelles very effectively reverse the MDR and enhance the therapeutic effect.

Zhao D ，Zhang H ，Yang S ，He W ，Luan Y ... -  《-》

Concurrently suppressing multidrug resistance and metastasis of breast cancer by co-delivery of paclitaxel and honokiol with pH-sensitive polymeric micelles.

To concurrently suppress multidrug resistance (MDR) and metastasis of breast cancer cells, paclitaxel (PTX) and honokiol (HNK) were coencapsulated into pH-sensitive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA). The physicochemical properties of dual drug-loaded PEOz-PLA micelles were characterized in size, drug loading and in vitro release. The efficiency of MDR reversal for the micelles was testified by synergetic enhancement of cytotoxicity and uptake by MCF-7/ADR cells. The flow cytometry and fluorescence polarization measurement results reinforced the conclusion that down-regulation of P-gp expression and increase of plasma membrane fluidity appeared to be possible mechanisms of MDR reversal by dual drug-loaded PEOz-PLA micelles. Further, the efficient inhibition of tumor metastasis by dual drug-loaded PEOz-PLA micelles was demonstrated by in vitro anti-invasion and anti-migration assessment in MDA-MB-231 cells and in vivo bioluminescence imaging in nude mice. The suppression of MDR and metastasis by the micelles was assigned to synergistic effects of pH-triggered drug release and HNK/PEOz-PLA-aroused P-gp inhibition, and pH-triggered drug release and PTX/HNK-aroused MMPs inhibition, respectively. In conclusion, our findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis. Multidrug resistance (MDR) and metastasis are considered to be two of the major barriers for successful chemotherapy. The combination of a chemotherapeutic drug with a modulator has emerged as a promising strategy for efficiently treating MDR cancer and preventing tumor metastasis. Herein, a dual drug (paclitaxel and honokiol)-loaded pH-sensitive polymeric micelle system based on PEOz-PLA was successfully fabricated to ensure that tumor MDR and metastasis could be concurrently suppressed, therefore achieving distinguishing endo/lysosomal pH from physiological pH by accelerating drug release and then enhancing the cytotoxicity of paclitaxel to drug-resistant tumor cells MCF-7/ADR by increasing cellular uptake of paclitaxel, preventing in vitro invasion and migration for MDA-MB-231 cells and in vivo metastasis in nude mice. Further, the mechanism of MDR reversal by dual drug-loaded PEOz-PLA micelles was elucidated to be down-regulation of P-gp expression and increase of plasma membrane fluidity of MCF-7/ADR cells. The present findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.

Wang Z ，Li X ，Wang D ，Zou Y ，Qu X ，He C ，Deng Y ，Jin Y ，Zhou Y ，Zhou Y ，Liu Y ... -  《-》