Investigation on vitamin e succinate based intelligent hyaluronic acid micelles for overcoming drug resistance and enhancing anticancer efficacy.

Multidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports have showed that vitamin E (VE) can cause significant reversal of MDR due to inhibition of ATPase activity. Accordingly, we synthesized hyaluronic acid (HA) conjugated vitamin E succinate (VES) polymer, which can self-assemble into micelles and thus achieve high drug (paclitaxel (PTX) used as model drug) encapsulation as well as tumor accumulation owing to the enhanced permeability and retention (EPR) effect and HA active targeting ability. In addition, the linker between HA and VES utilized in this work was disulfide bond with reduction-sensitive property, which would respond to high glutathione (GSH) concentration in tumor cytoplasmic environment and trigger HA-CYS-VES polymer disassociation and drug release. In vitro, PTX loaded HA-CYS-VES demonstrated enhanced cytotoxicity, high apoptosis-inducing activities and reversal effects of PTX on MCF-7/Adr cells, compared to PTX. Also, cellular uptake and intracellular PTX accumulation tests displayed that PTX loaded HA-CYS-VES could more efficiently enter tumor cells and selectively release drug in cytosol so as to facilitate its function on microtubule. More importantly, PTX loaded HA-CYS-VES showed better tumor targeting ability, improved antitumor efficacy and low adverse effects on tumor-bearing mice. In conclusion, PTX loaded HA-CYS-VES exhibited a great potential for reversing MDR in anticancer chemotherapeutics.

Hou L ，Tian C ，Chen D ，Yuan Y ，Yan Y ，Huang Q ，Zhang H ，Zhang Z ... -  《-》

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 ... -  《-》

The effect of dual-functional hyaluronic acid-vitamin E succinate micelles on targeting delivery of doxorubicin.

Wang J ，Ma W ，Guo Q ，Li Y ，Hu Z ，Zhu Z ，Wang X ，Zhao Y ，Chai X ，Tu P ... -  《International Journal of Nanomedicine》

Paclitaxel delivered by CD44 receptor-targeting and endosomal pH sensitive dual functionalized hyaluronic acid micelles for multidrug resistance reversion.

The drug efflux mediated by P-glycoprotein (P-gp) transporter is a major factor responsible for multidrug resistance (MDR) of paclitaxel (PTX). The efficient intracellular PTX delivery is a promising strategy for overcoming the MDR of tumor cells. A CD44 receptor targeting and endosome-pH sensitive dual functionalized hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar formulation was developed to overcome MDR, and a CD44 receptor targeting hyaluronic acid-deoxycholic acid (HA-DOCA) micelles was used as a comparison. Compared with Taxol solution and HA-DOCA micelles, the cytotoxicity of PTX loaded in HA-DOCA-His micelles against drug-resistant tumor cells was improved significantly and possessed superior MDR-overcoming performance; this phenomenon is due to the increased intracellular PTX delivery by CD44 receptor-mediated endocytosis pathway and endosome-pH sensitivity-mediated PTX triggering release. Upon pharmacokinetic study, PTX/HA-DOCA-His micelles demonstrated longer blood circulation time, larger AUC, decreased Vd and CL than the Taxol solution. More importantly, PTX/HA-DOCA-His micelles were more effective in tumor growth inhibition in MCF-7/Adr tumor-bearing mice compared with PTX/HA-DOCA micelles and Taxol solution. Dual targeting strategy-functionalized HA-DOCA-His micelles demonstrated excellent MDR-reversing ability for therapeutic efficacy and improvement on MDR tumors, thereby providing an effective targeting strategy for PTX delivery of nano-drug delivery system in MDR cancer chemotherapy.

Liu Y ，Zhou C ，Wei S ，Yang T ，Lan Y ，Cao A ，Yang J ，Hou Y ... -  《-》

Paclitaxel-loaded redox-sensitive nanoparticles based on hyaluronic acid-vitamin E succinate conjugates for improved lung cancer treatment.

Song Y ，Cai H ，Yin T ，Huo M ，Ma P ，Zhou J ，Lai W ... -  《International Journal of Nanomedicine》